AU2013276985B2 - Antimicrobial and antiviral compounds and methods for their use - Google Patents

Abstract

The present invention provides protonated compounds having antiviral and antimicrobial activity. The invention also provides antimicrobial compositions comprising protonated compounds of the invention. The protonated compounds of the invention provide efficacious antimicrobial activity against i esistant strains of bacteria and opportunistic fungi. The invention also provides antiviral compositions comprising compounds of the invention. Viruses that may be treated by compositions of the invention include, but are not limited to, HIV, HSV, CMV, HBV, HCV and influenza virus

Description

P100/011 Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Antimicrobial and antiviral compounds and methods for their use The following statement is a full description of this invention, including the best method of performing it known to us: ANTIMICROBIAL AND ANTIVIRAL COMPOUNDS AND METHODS FOR THEIR USE FIELD OF THE INVENTION 100011 The invention relates generally to the field of therapeutics used to treat bacterial, fingal and viral infections. The invention relates generally to the field of protonated chemicals and specifically to protonated compounds used as pH stabilizers and therapeutics containing such molecules. CROSS-REFERENCE TO RELATED APPLICATIONS [00021 This application is a continuation-in-part of U.S. Patent Application Serial No. 10/937094, filed September 8, 2004 which is a continuation of U.S. Application Serial No. 09/847654, filed on May 3, 2001, which is in turn a continuation-in part of U.S. Patent Application Serial No.: 09/281,858 filed March 31, 1999, which application is a continuation-in-part of U.S. Patent Application Serial No.: 09/222,009 filed December 30, 1998, all of which are herein incorporated by reference in their entirety. BACKGROUND OF THE INVENTION 100031 Pathogenic bacteria responsible for infectious diseases were once thought to be controllable through the use of a battery of antibiotics such as penicillin, streptomycin, tetracycline, and others. However, since the widespread use of antibiotics began in the 1950s, more and more bacteria have evolved to become resistant to one or more antibiotics. Multiple drug-resistant strains are increasingly common, particularly in hospitals. 10004] Currently, nosocomial Staphylococcal infections exhibit multiple drug resistance. See, for example, Archer et al., 1994, Antimicrob. Agents Chemother. 38:2231-2237. At this time, the remaining antibiotic that demonstrates the ability to kill most strains of Staphylococci is vancomycin. However, vancomycin resistant strains of both Staphylococcus and Enterococcus have already been isolated and reported by Zabransky et al., 1995, J. Clin. Microbiol 33(4):791-793. Furthermore, transfer of resistance from Enterococci to Staphylococci has been previously documented by Woodford et al., 1995, J. Antimicrob. Chemother. 35:179-184. Streptococcus pneumoniae is a leading cause of morbidity and mortality in the United States (M.M. W.R., Feb. 16, 1996, Vol. 45, No. RR-1). Each year these bacteria cause 3,000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7,000,000 cases of otitis media. Case fatality rates are greater than 40% for bacteremia and greater than 55% for meningitis, despite antibiotic therapy. In the past, Streptococcus pneumoniae were uniformly susceptible to antibiotics; however, antibiotic resistant strains have emerged and are becoming widespread in some communities. [00051 In addition, there are instances where antibiotic resistance is not an issue, yet a particular bacterium remains refractory to treatment using conventional antibiotics. Such is the case with Escherichia coli 0157:H7, a causative agent for food poisoning and death from undercooked meat. The Department of Agriculture estimates that 10 people die each day and another 14,000 become ill due to this bacterium. Unfortunately, conventional antibiotics are completely ineffective against this organism. [00061 The history of antibiotic treatment of pathogenic bacteria is cyclical. Bacteria are remarkably adaptive organisms, and, for each new antibiotic that has been developed, resistant bacterial strains arise through the widespread use of the antibiotic. Thus, there is a constant need to produce new antibiotics to combat the next generation of antibiotic-resistant bacteria. Traditional methods of developing new antibiotics have slowed, and in the past two years, only one new antibiotic 1A has been approved by the FDA. Furthermore, according to Kristinsson (Microb. Drug Resistance 1(2):121 (1995)), "there are no new antimicrobial classes with activity against resistant Gram positives on the horizon." 100071 There is a need for a compound that provides a compositional environment that will allow an increase in the efficacy of known antibacterial agents. There is also a need in the art for a compound that facilitates the activity of an active antibacterial agent, thus allowing the use of a lower amount or dose of antibiotic while reducing the development of resistant bacterial strains. [00081 Viral disease is another health related disease state which threatens large segments of human populations. Some of the features related to viral infection which are of concern to health care professionals include its highly contagious nature (i.e., HIV, SARS etc) and high mutability. Some viruses are also oncogenic (such as HPV, EBV and HBV). While viruses are structurally amongst the simplest of organisms, they are regarded to be among the most difficult to control and present a formidable challenge for antiviral drug R&D. 100091 Thus far, there have been a few antiviral drugs widely used in patients, such as Amantadine for flu, Acyclovir for HSV-related infections, Ganciclovir for CMV infection, and AZT, DDI and d4T for AIDS treatments. These drugs possess a variety of undesirable neurological, metabolic and immunological side-effects. Therefore, development of new antiviral therapy has become a major focus of medical and pharmaceutical research and development. 100101 Nucleosides are natural metabolic products and precursors in human and animals. Modified nucleosides may have much lower toxicity to humans and thus have potential for use as safer antiviral drugs. SUMMARY OF THE INVENTION 100111 The present invention provides molecules having antimicrobial activity, which molecules have two end blocks and at least one proton acceptor site. The invention also provides for compositions of the invention comprising a protonated antimicrobial compound and an excipient. The protonated compounds of the invention can be used as the sole active agent in the composition, or may be used in conjunction with another active agent to enhance the efficacy of compositions against resistant strains of bacteria and opportunistic fungi. 100121 The structure of the compounds of the invention is X-Y-Z, where X and Z are end blocking groups, preferably alkyls or 0-alkyls, which may be the same or different, and Y is a phosphorous containing molecule with protonation sites. [00131 In a preferred embodiment, Y is one or more substituted or unsubstituted phosphate groups. Exemplary structures of this embodiment have a Y structure as follows (Structures 1 and 2): 0 OX1 P--Z OH Structure 1 2 O O OX-P-ORO-P-OZ OH OH Structure 2 [00141 where X and Z are end blocking groups, which may be the same or different, and R is a dysfunctional alkyl, aryl, alkenyl (preferably containing 1-20 carbons, more preferably 1-6 carbons), or some combination of the three (e.g., a difunctional alkyl, aryl, alkenyl, alkylaryl, alkylalkenyl, arylalkenyl or alkylarylalkenyl group), as a derivative of primary, secondary or tertiary alcohols; phenols; or enols either separately or in any combination. It may be monocyclic, polycyclic, heterocyclic or linear in form, either separately or in any combination of forms. It may have free alcoholic or phenolic hydroxyls in addition to the two converted into phosphodiesters. There may be other functional groups such as but not limited to amines, carboxylates, carboxyaldehydes, ketones, and the structure may be modified by the addition of halogens or other groups intended to modify the electronegativity of the structure of the molecule. [00151 In another embodiment, Y is a sugar structure, preferably pentose or hexose, flanked by substituted or unsubstituted phosphate groups. Examples of such sugar groups can be seen in Structures 3A, 3B below: O || OH--P--_ W Q OX H H H H O OA OH---P==O Oz Structure 3A 0 OH--P--O W IIQ OX H H H H O A OH-P=O Oz Structure 3B 3 wherein: Q is 0, S, P-H, P-OH, P-alkyl, P-aryl, P-acyl, N-H, N-OH, N-alkyl, N-aryl, or N-acyl; A is H, alkyl, or alkyl-(O-alkyl), aryl, alkenyl, alkanol, phenol, or enol; X and Z are end blocking groups that may be the same or different; and W is H, or a purine or pyrimidine, or a modified analogue of a purine or pyrimidine. Further examples of such sugar groups can be seen in Structures 4A and 4B below: O OHP---OW Oz O OCH3 HO-P=O Oz Structure 4A 0 O Q W HO -\ Ox O v OCH 3 HO-P- O Oz Structure 4B wherein: V or Q is independently 0, S, P-H, P-OH, P-alkyl, P-aryl, P-acyl, N-H, N-OH, N-alkyl, N-aryl, or N-acyl, -CH2, -CH(OH)-,-CH2(0-alkyl)-; X and Z are end blocking groups that may be the same or different; and W is H, or a purine or pyrimidine, or a modified analogue 4 of a purine or pyrimidine. [00161 In a preferred embodiment, Q and/or V independently may be -CH 2 -, -CH(OH)-, or -CH(O-alkyl)-. [00171 In a preferred embodiment, the sugar is a pentose molecule with a substitution at the 2 carbon site (hereafter "2-R substituted" and the like), as illustrated as Structure 5: 0 P-- W HO Q ox H H H 0 0

OCH

3 "0/ >o'z HO O Structure 5 Wherein Q is 0, S, P-H, P-OH, P-alkyl, P-aryl, P-acyl, or N-H; and W, X and Z are as stated above. The X and Z groups are chemical moieties that provide stability. The end blocking groups may be any number of chemical entities, provided the end block prevents degradation of the molecule. In one embodiment, the end blocks are alkyl or O-alkyl, where the alkyl moiety can be straight chained, branched or cyclic but is preferably a straight chain containing 1-4 carbons. X and Z may be the same chemical moiety (e.g., butyl groups) or two different chemical moieties (e.g., X is a butyl group and Z is a butanol). In some embodiments, X and Y are independently

CH

3

CH

2

CH

2

CH

2 -, CH 3

CH

2 CH2-, CHCH2-, HO- CH 2

CH

2

CH

2

CH

2 -, XO- CH 2

CH

2

CH

2

CH

2 -, or YO- CH 2

CH

2

CH

2

CH

2 -. 100181 In a specific embodiment, the compound is a protonated molecule having end blocking groups to prevent degradation, and a sugar group with a 2-R or 2-OR modification. One example of such a molecule is shown as Structure 5. The protonated compounds of the invention are acidified to give a pH when dissolved in water of less than pH 6 to about 1, more preferably less than pH 4.5 to -about 1, and even more preferably less than pH 3 to about 2. By introducing the modifications such as these to the compounds of the invention, the compounds are rendered more acid and nuclease resistant. Percent acid degradation may be determined using analytical HPLC to assess the loss of functional molecules, or by other suitable methods. The compounds of the invention are 10%, 20%, 30%, 40%, 50%, 70%, 90%, 100%, 150%, 200%, 300%, 500%, 750%, or 100% more stable than a reference compound. [0019] In one aspect of the invention, the compounds of the invention are incorporated into liposomes. In some embodiments of the invention, neutral lipids, cholesterol, and/or polyethylene glycol (PEG) are utilized in the liposomes. In some embodiments the liposomal composition is composed of partially hydrogenated soy phosphatidylcholine (PHSC), cholesterol, methoxy-terminated PEG (mPEG), and/or distearoyl phosphatidyl ethanolanine (DSPE). In some embodiments 5 the ratio of PHSC:mPEG: DSPE may be in the range of about 40:50:10 w/w% to about 60:30:10 w/w% or to about 60:35:5 w/w%. In some embodiments the percentage of PHSC is in the range of about 40% to about 60w/w% of the total lipid content. In some embodiments the percentage of mPEG is in the range of about 25% to about 45 w/w% of the total lipid content. In some embodiments the percentage of DSPE is in the range of about 3% to about 15w/w/o of the total lipid content. In other embodiments, the liposome formulation comprises of partially hydrogenated soy phosphatidylcholine (PHSC), cholesterol, and methoxy-terminated PEG (mPEG). In some embodiments the ratio of PHSC:cholesterol: mPEG may be in the range of about 40% to about 60w/w/o PHSC, about 30% to about 40w/w% cholesterol, and about 5% to about 1Ow/w/o mPEG. In some other embodiments, the liposome formulation comprises about 56% PHSC, about 38% cholesterol and about 6% mPEG. In some embodiments of the invention, the liposomes have a particle size of about 60nm to about 120 mu diameter. In other embodiments of the invention, the liposomes have a particle size of about 75 nm to 110 nm, or about 80 nm to about 100 nm. The ratio of a compound of the invention to lipids in the liposomal composition may be about 1: 9w/w to about 1:3w/w. In some embodiments the ratio of a compound of the invention to lipids in the liposomal composition may be about 1:5w/w to about 1:3w/w. The liposomal compositions of the invention may further contain one or more excipients. 100201 The invention also provides methods for inhibiting or preventing the growth of bacteria, fungus, or virus, by contacting the infectious organism with a composition comprising a protonated compound of the present invention. In some embodiments the methods are used to treat a mammal. In some embodiments, the methods are used to treat a human. [00211 The invention provides methods using compounds of the invention to treat a mammal suffering from a bacterial infection caused by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Mycobacterium and Escherichia coli, Aerococcus, Listeria, Streptomyces, Chlamydia, Lactobacillus, Eubacterium, Arachnid, Mycobacterium, Peptostreptococcus, Corynebacterium, Erysipelothrix, Dermatophilus, Rhodococcus, Pseudomonas, Streptococcus, Bacillus, Peptococcus, Pneumococcus, Micrococcus, Neisseria, Klebsiella, Kurthia, Nocardia, Serratia, Rothia, Escherichia, Propionibacterium, Actinomyces, Helicobacter, Enterococcus, Shigella, Vibrio, Clostridium, Salmonella, Yersinia, or Haemophilus. An embodiment of the invention provides a method of treating a mammal suffering from a bacterial infection by administering a liposomal composition comprising the compound of Formula 1 and a lipid. c X0 3-0~-cu z H H IH LH A HO0-P=O Y Formula I 100221 The invention provides methods using compounds of the invention to treat a mammal suffering from a fungal infection caused by Trichophyton, Epidermophyton, Microsporum, Candida, Pityrosporum, Trichophyton, or Epidermophyton. An embodiment of the invention provides a method of treating a mammal suffering from a fungal infection by administering a liposomal composition comprising the compound of Formula 1 and a lipid. 6 0 xo --- ocH H H HOLH Y Formula I 100231 The invention provides methods using compounds of the invention to treat a mammal suffering from a viral infection caused by HIV, HSV, CMV, HBV, HCV or influenza virus. An embodiment of the invention provides a method of treating a mammal suffering from a viral infection by administering a liposomal composition comprising the compound of Formula 1 and a lipid. 0* X0 It Xo -P-O-CH 2 Z 0 A HO-P0o Y Formula I [00241 In some embodiments of the invention the liposomal compositions are administered to a mammal orally. In some embodiments of the invention the liposomal compositions are administered to a mammal topically. In some embodiments of the invention, the liposomal compositions of the invention are administered to a mammal via aerosol. In some embodiments of the invention the liposomal compositions of the invention are administered via injection. 100251 Administration of the composition will introduce the compounds of the invention to the mammal in a diluted amount. Exemplary unit dosages for oral, injectable, aerosol, or topical administration may be more than about 0.01, 0.05, 0.1, 0.5, 1, or 5 mg/kg, and/or less than about 10, 5, 1, 0.5, 0.1, or 0.05 mg/kg. Exemplary unit dosage ranges may be between about 0.01 mg/kg and 10 mg/kg, or between about 0.010 mg/kg and 1.0 mg/kg, or between about 0.10 mg/kg and 1.0 mg/kg. In some embodiments, the compositions of the invention are administered at unit dosages of about 0.01 to about 100 ug per kg of body weight, or about 0.1 to about 100 ug per kg of body weight, or about 0.1 to about 10 ug per kg of body weight, or about 1 to about 10 ug per kg of body weight, or about I to about 5 ug per kg of body weight. In some embodiments, unit dosages of the composition of the mvention are at or below 100 ug per kg of body weight, or at or below 10 ug per kg of body weight, or at or below 1 ug per kg of body weight, or at or below 0.1 ug per kg of body weight, or at or below 0.01 ug per kg of body weight. 10026] In some embodiments of the invention, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. In some embodiments, a patient is instructed to take two to three dosage units per day. 7 [0027] In some embodiments, the invention provides homeopathic compositions. Homeopathic compositions may be made by methods known in the art. One exemplary method of making a homeopathic composition comprises (i) triturating solid compound of the invention in a 1/9 ratio with lactose to produce a 1X solid and (ii) repeating the process until the desired attenuation is achieved. In a related vein, a method of making a homeopathic composition comprising (i) dissolving 1 part compound of the invention by weight in liquid to produce ten volumes of liquid attenuation labeled IX and optionally (ii) mixing I ml of the IX attenuation with 9 ml of diluent to produce a lower concentration, is also addressed. 100281 The invention specifically provides therapeutic methods of using protonated compounds as inactive ingredients in topical compositions containing an active ingredient, e.g., an antibiotic, antifungal, or antiviral. The preferred method of treatment comprises the administration of the protonated compounds with an appropriate excipient to an animal. For example, the protonated compounds are administered to alleviate the symptom of the bacterial growth, or in an amount effective for treatment of a bacterial infection. 100291 The invention further provides the use of the protonated compounds as an inactive biostatic or biocidal preservative in compositions, in conjunction with an acceptable pharmaceutical carrier, to prepare medicinal compositions for the treatment of bacterial infections in animals, and more preferably mammals, including humans. [00301 The invention further provides the use of the protonated compounds as an active ingredient having antifungal properties against infectious agents such as Candida albicans and Trichophyton. 100311 The invention further provides the use of the protonated compounds as an active ingredient having antiviral properties against infectious agents such as herpes simplex found in cold sores. [00321 The invention further provides the use of the described protonated compounds as active ingredients in a topical skin cream with an acceptable cosmetic carrier. Such topical skin creams may contain additives such as emollients, moisturizers, fragrance, and the like. 100331 The invention further provides disinfectant solutions comprised of the described protonated compounds. The disinfectant may be suitable for use on skin, due to the non-toxicity of the protonated compounds, or may be used for disinfection of a surface such as medical devices, e.g. a surgical instrument. 100341 It is an object of the invention to use protonated compounds in conjunction with one or more antibacterial agents to inhibit the growth of any bacteria, including clinically relevant pathogenic bacteria. 100351 It is an advantage of the invention that the mechanism of action of the activity of the protonated compounds is effective against any bacterium including clinically relevant pathogenic bacteria, both gram positive and gram negative. [00361 It is another advantage of the invention that the protonated compounds are non-toxic to a subject treated with the a composition containing the protonated compounds [0037] These and other objects, advantages, and features of the invention will become apparent to those skilled in the art upon reading the details of the protonated compounds and uses thereof as more fully described below. BRIEF DESCRIPTION OF THE DRAWINGS [00381 Figure 1 illustrates the chemical structure of exemplary molecules of a preferred embodiment of the invention. [00391 Figure 2 illustrates alkyl phosphate structures that may be used as the central group (Y) in the compounds of the invention; X and Z are end blocking groups that may be the same or different. 100401 Figure 3 illustrates exemplary sugar structures of the central group (Y) of molecules of the invention. 8 [00411 Figure 4 illustrates exemplary single ring chemical moieties (W) that may be attached to a sugar group in the central group (Y) in the present invention. 100421 Figures 5 and 6 illustrate exemplary double and multiple ring chemical moieties (W) that may be attached to a sugar group in the central group (Y) in the present invention. 10043] Figure 7 illustrates exemplary partially or totally hydrogenated chemical moieties (W) that may be attached to a sugar group in the central group (Y) in the present invention. 100441 Figure 8 illustrates an exemplary oxidized ring structure (W) that may be attached to a sugar group in the central group (Y) in the present invention. 100451 Figure 9 illustrates an exemplary proton acceptor substituent (W) that may be attached to a sugar group in the central group (Y) in the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENTS 100461 It is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which will be limited only by the appended claims. 100471 It must be noted that as used herein and in the appended claims, the singular forms a, and, and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to bacteria includes a plurality of bacteria species and a protonated compound may encompass a plurality of such compounds and equivalents thereof known to those skilled in the art, and so forth. [00481 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described. [00491 All publications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the active antibiotic agents, composition carriers, and methodologies that are described in the publications which might be used in connection with the presently described invention. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission.that the inventors are not entitled to antedate such disclosure by virtue of prior invention. Definitions 100501 The term "antimicrobial" refers to an ability to kill or inhibit the growth of microorganisms (including, without limitation, viruses, bacteria, yeast, fungi, protozoa, etc.), or to attenuate the severity of a microbial infection. The antimicrobial compounds of the present invention are compounds that may be used in the treatment of disease and infection. 10051] The term "protonation" and "acidification" as used interchangeably herein refers to the process by which protons (or positively charged hydrogen ions) are added to proton acceptor sites on a compound of the invention. The proton acceptor sites include the substituted or unsubstituted phosphates of the central group, as well as any additional proton acceptor sites on either the central group or the end blocking groups. As the pH of the solution is decreased, the number of these acceptor sites which are protonated increases, resulting in a more highly protonated compound. 9 [00521 The term "protonated compound" refers to a molecule of the invention that, when dissolved in water having a pH of 7 causes the pH of the solution to fall. Generally, compounds are protonated by adding protons to the reactive sites on the molecule, although other modifications of the molecule are possible, and are intended to be encompassed by this term. Such protonization can be accomplished, for example by incubating the compound in the presence of a strong acid, most preferably one with a volatile conjugate base. [00531 The term "end group" and "end blocking group," as used herein refers to any chemical moiety that prevents substantial nuclease degradation, and in particular exonuclease degradation, of a protonated compound. The end group may be any chemical moiety that allows for proper protonation of the compound, including H, OH, SH, NH2, an alkyl group, an alkanol group, and the like. In a specific embodiment, the chemical modification is positioned such that it protects the central group of the molecule, i.e. the blocking group is the X or Z that protects the central group Y of the X-Y-Z structure. The end group(s) and/or end-blocking group(s) of an X-Y-Z molecule may be the same or different. 100541 The term "active agent" as used herein, refers to compounds with known activity for the treatment of disease caused by microbes, and in particular agents that are effective in sublingual, intraocular, intraaural, and particularly topical, application. 100551 Central or end groups may contain chemical moieties such as phosphodiesters, methylphosphonates, ethylphosphotriesters, methylphosphorothioates, methyl-p-ethoxy groups, methyls, alkyls, O-alkyls, 0-alkyl-n(O-alkyl), fluorines, deoxy-erythropentofuranosyls, methyl ribonucleosides, methyl carbamates, methyl carbonates, inverted bases (e.g., inverted T's), etc. In one preferred embodiment, these chemical moieties contain oxygen linkages groups, e.g. O-methyl or O-alkyl-n(0-alkyl). 100561 The term "alky!" as used herein refers to a straight chain, cyclic, branched or unbranched saturated or unsaturated hydrocarbon chain containing 1-20 carbon atoms (preferably 1-6), such as methyl, ethyl, propyl, tert-butyl, n-hexyl and the like. 10057] The term "alkanol" as used herein refers to a branched or unbranched hydrocarbon chain containing 1-6 carbon atoms and at least one -OH group, such as methanol, ethanol, propanol, isopropanol, butanol, and the like. [00581 The terms "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease (or infection) and/or adverse effect attributable to the disease (or infection). "The terms "treatment", "treating" and the like as used herein includes: (a) preventing a microbial disease and/or infection from occurring in a subject who may be predisposed to but has not yet been diagnosed as having it; (b) inhibiting the progress or transmission of a microbial disease and/or infection, i.e., arresting its development or maintenance; or (c) relieving a bacterial disease (i.e., causing regression and/or amelioration of the disease) and/or infection. The term "treatment" further comprises preventing inhibiting or relieving the symptoms of a disease resulting from infection by a microbe. The invention is particularly directed toward treating patients with any infectious bacteria or fungi; in a mammal, and particularly in a human mammal. 10059] The present invention employs protonated compounds as antimicrobial agents, and in particular as antimicrobial agents having activity against bacteria, fungi, protozoa and viruses. These compounds are particular useful in medical 10 applications, both allopathic and homeopathic. The bacteriocidal/bacteriostatic effect also allows use of these compositions in compositions for sterilization (e.g., sterilization of skin or of a surface or an object such as a surgical instrument, etc.), or sanitization (e.g., the cleansing of a surface, instrument, etc. so as to render it free of undesirable concentrations of disease causing microorganisms (including viruses). In addition, the protonated compounds themselves in specific concentrations have an antimicrobial preservative effect, and thus are also useful in preventing unwanted microbial growth in compositions. I. Detailed Description of the Compounds of the Invention. A. The Structures of the Compounds of the Invention. 10060] The protonated compounds of the invention have a structure as follows: X-Y-Z [00611 where Y is a structure comprising oxygen, phosphorous, and optionally carbon and X and Z are end groups comprising a blocking agent. The end groups X and Z may be the same chemical moiety, or they may be different. [00621 In a preferred embodiment, Y is one or more substituted or unsubstituted phosphate groups. Exemplary structures of this embodiment have a Y structure as follows (Structures 1 and 2): O OX-P-OZ OH Structure 1 O O OX-P-ORO-- OZ I I OH OH Structure 2 [00631 where X and Z are end blocking groups, which may be the same or different, and R is a difunctional alkyl, aryl, alkenyl (preferably containing 1-20 carbons, more preferably 1-6 carbons), or some combination of the three, as a derivative of primary, secondary or tertiary alcohols; phenols; or enols either separately or in any combination. It may be monocyclic, polycyclic, heterocyclic or linear in form, either separately or in any combination of forms. It may have free alcoholic or phenolic hydroxyls in addition to the two converted into phosphodiesters. There may be other functional groups such as but not limited to amines, carboxylates, carboxyaldehydes, ketones, and the structure may be modified by the addition of halogens or other groups intended to modify the electronegativity of the structure of the molecule. [0064] Examples of molecules that are intended to be encompassed by the above-described structures include: 11 0 O

CH

3

CH

2

CH

2

CH

2 0-P-OCH 2

CH

2

CH

2

CH

2 0-P-OCH 2

CH

2

CH

2

CH

3 OH OH O 0

CH

3

CH

2

CH

2

CH

2 0-P- OCH 2

CH

2 0CH 2

CH

2 0- P- OCH 2

CH

2

CH

2

CH

3 II OH OH O O

CH

3 CH20-P--OCH 2

CH

2 -- OCH 2

CH

3 I I OH OH O O

CH

3

CH

2 0--P---OCH 2

CH

2

CH

2

CH

2 0--P--OCH 2

CH

3 OH OH O O

CH

3

CH

2

CH

2

CH

2

-OCH

2

CH

2 0 P-OCH 2

CH

2

CH

2

CH

3 OH OH

XOCH

2

CH

2

CH

2

CH

2 0-P-OCH 2

CH

2

CH

2

CH

2 OZ OH O O

XOCH

2

CH

2

CH

2

CH

2 0--P--OCH 2

CH

2

CH

2

CH

2 0-P--OCH 2

CH

2

CH

2

CH

2 OZ OH OH [0065] A particularly preferred example of such compounds is Nu-5: 12 O O

CH

3

CH

2

CH

2

CH

2 0-P-OCH 2

CH

2

CH

2

CH

2 0-P-OCH 2

CH

2

CH

2

CH

3 I I OH OH [00661 In another embodiment, Y is a sugar structure, preferably pentose or hexose, flanked by substituted or unsubstituted phosphate groups. Examples of X-Y-Z compounds containing such Y sugar groups are illustrated below: 0 OH-P-- W Q ox H H H H O OA OH-P O Oz 100671 and 0 OH-P-- W Q ox H H H H O A OH-P-O Oz Wherein Q is 0, S, P-H, P-OH, P-alkyl, P-aryl, P-acyl, N-H, N-OH, N-alkyl, N-aryl, or N-acyl; A is H, alkyl, alkoxy, or alkyl-(O-alkyl), aryl, alkenyl, alkanol, phenol, or enol; X and Z are end blocking groups that may be the same or different; and W is H, or a purine or pyrimidine, or a modified analogue of a purine or pyrimidine. 100681 Preferred examples of such compounds have X or Z blocking groups, which independently comprise a structure selected from the group consisting:

CH

3

CH

2

CH

2

CH

2 - CH 3

CH

2 CH- ; CH 3

CH

2 HO-CH 2

CH

2

CH

2

CH

2 - ; XO-CH 2

CH

2

CH

2

CH

2 - ; and

ZO-CH

2

CH

2

CH

2

CH

2 - . [00691 Preferred examples of such compounds have an A group, which comprises a structure selected from the group consisting: - H; - CH 3 ; - OCH 2

CH

2

OCH

2 CH3; and - OCH 2

CH

3 . 13 [00701 Further examples of X-Y-Z compounds containing such Y sugar groups are illustrated below. 0 OH O Q W Oz O OCH3 HO-P=O Oz and c\\O Q W HO Ox O V OCH 3 HO-P-O Oz Wherein: V or Q is independently 0, S, P-.H, P-OH, P-alkyl, P-aryl, P-acyl, N-H, N-OH, N-alkyl, N-aryl, N-acyl,-CH2-, CH(OH)-, -CH(O-alkyl)-; X and Z are end blocking groups that may be the same or different; and W is H, or a purine or pyrimidine, or a modified analogue of a purine or pyrimidine. [0071] Preferred examples of such compounds have X or Z blocking groups, which independently comprise

CH

3

CH

2

CH

2 CH- ; CH 3

CH

2

CH

2 - ; CH 3 CHr

HO-CH

2

CH

2

CH

2 CH- ; XO-CH 2

CH

2

CH

2

CH

2 - ; or

ZO-CH

2

CH

2

CH

2

CH

2 -. [00721 In a preferred embodiment, the sugar is a pentose molecule with a substitution at the 2 carbon site (hereafter "2-R substituted" and the like), as illustrated as Structure 5: 0 HO\ OX H H H H

OCH

3 \ / HO/ "-,oz HO O Structure 5 Q is 0, S, P-H, P-OH, P-alkyl, P-aryl, P-acyl, or N-H; W, X and Z are as stated above. 14 100731 The X and Z groups are chemical moieties that provide stability. The end blocking groups may be any number of chemical entities, provided the end block prevents degradation of the molecule. In one embodiment, the end blocks are alkyl or O-alkyl, where the alkyl moiety can be straight chained, branched or cyclic but is preferably a straight chain containing 1-4 carbons. X and Z may be the same chemical moiety (e.g., butyl groups) or two different chemical moieties (e.g., Z is a butyl group and X is a butanol). 10074] Preferred examples of such compounds have X or Z blocking groups, which independently comprise

CH

3

CH

2

CH

2

CH

2 - CH 3

CH

2

CH

2 - ; CH 3

CH

2 HO-CH 2

CH

2

CH

2

CH

2 - ; XO-CH 2

CH

2

CH

2

CH

2 - ; or

ZO-CH

2

CH

2

CH

2

CH

2 -. 100751 A particularly preferred example of such compounds is the compound Nu-2 ((4-hydroxybutyl)-phosphate-5'-uridine 2'-methoxy-3'-phosphate-(4-hydroxybutyl)): 0 NH cHCH 2

CH

2 CH20- P- - N 0 OH H H H O OCH 3 HO OCH 2

CH

2

CH

2

CH

2 OH Nu-2 [0076] A further particularly preferred example of such compounds is the compound Nu-3 (butyl-phosphate-5'-thymidine 3'-phosphate-butyl): 0 NH cHcH 2 cH2CH20- -o o N H H/ OCH 2

CH

2 cH 2

CH

3 Nu-3 [00771 A further particularly preferred example of such compounds is the compound Nu-4 (butyl-phosphate-5'-ribose-3' phosphate-butyl): 15 O

CH

3

CH

2

CH

2

CH

2 0 O H OH H H H H /0 H H/ OCH 2

CH

2

CH

2

CH

3 Nu-4 [00781 In one embodiment of the invention, the protonated compound has a sugar group, preferably either a ribose or a glucose group. The sugar structure of the molecules of the invention may be modified from that of a naturally occurring sugar, i.e. the overall structure of the sugar group is maintained, but one or more residues of the sugar is substituted and/or the sugar structure contains an additional residue compared to the unsubstituted form. See T.W. Graham Solomons, Organic Chemistry, J. Wiley and Sons,'6th edition (July 1998), pp. 937-971 for examples of sugar structures that may be used in the protonated compounds of the present invention. 100791 "W" as used in the structures and drawings of the present invention is a purine or pyrimidine, or a modified analogue of a purine or pyrimidine. Figures 4-8 illustrate exemplary substituent groups (W) that may be added to the naturally occurring structure of the sugar group for use in protonated compounds of the present invention. Such compounds (W) include, but are not limited to, modified analogues of purines and pyrimidines that do not form Watson-Crick base pairing with the naturally occurring bases, such as 2-aminoadenosine, theobromine, caffeine, theophylline, and uric acid; structures based on single ring structures such as pyridine, pyrazine, or triazine (Figure 4): N N N N N N Figure 4 structures based on multi-ring structures such as indole, acridine, indazole, phenoxazine, phenazine, phenothiazine, quinoline, isoquinoline, quinazoline, and pteridine (Figure 5): 16 N quinoline isoquinoline N N N N N quinazoline pteridine Figure 5 partially or totally hydrogenated single and multi-ring structures (Figure 6): N N N H H N indole indazole acridine S 0 N N N: N I Ii phenothiazine phenoxazine phenazine Figure 6 partially oxidized single and multi-ring structures, e.g., caprolactam (Figure 7): N 0 Figure 7 structures with proton acceptor substituents, e.g. nitrogen-containing heterocyclics such as leucomethylene blue (Figure 8): 17

(CH

3

)

2 N. S N(CH 3

)

2 N leucomethylene blue Figure 8 and other structures that have similar electron configurations to purines and pyrimidines. 100801 Each of these substituents may be further modified with electron withdrawing or donating groups, halogens, alcohols, diols, phosphorus amides, and phosphonic acids and the like to adjust the proton acceptance capability and/or other characteristic of the compound. Although the structure W is illustrated as being substituted at the 1 carbon site of the sugar molecule, the W structure may be linked to a different site, e.g., the 2 or 3 carbon site of the sugar group. [00811 Substituents are in general selected to enhance one or more effects of the compound, e.g., to enhance pH, decrease toxicity and the like. Particular chemical moieties that are selected as central groups in the protonated compounds will be easily identified by one skilled in the art upon reading the present disclosure, and such moieties can be found in references such as T.W. Graham Solomons, Organic Chemistry, J. Wiley and Sons, 6th edition (July 1998); S. F. Sun, Physical Chemistry of Macromolecules: Basic Principles and Issues (1994); J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th edition (August 1992); and L. Stryer, Biochemistry, 4th edition (March 1995). [00821 The compounds of the invention are synthesized using organic chemical synthetic methods known in the art. See, e.g., Example 7. B. The Protonated Compounds of the Invention and Selected Physical Properties. 1. Generation of the Protonated Compounds [00831 Protonation of the compounds of the invention is the process by which protons (or positive hydrogen ions) are added to the reactive sites on the molecule. As the number of reactive sites that are protonated increases, the pH obtained when the compounds are dissolved in water having a pH of 7 decreases, and thus the amount of protonation of the compounds of the invention can be determined by measuring the pH of solutions of water after addition of the compounds of the present invention. Preferably, the compounds of the present invention are protonated so that when dissolved in water (pH 7), they form an aqueous solution having a pH of between less than pH 7 to about 1, preferably between less than about pH 6 to about 1, and more preferably between less than about pH 5 to about 1. In a more preferred embodiment, the compounds of the present invention are protonated so that when dissolved in water (pH 7), they form an aqueous solution having a pH of between less than about pH 4.5 to about 1, preferably between less than about pH 4 to about 1, more preferably between less than about pH 3 to about 1, and still more preferably less than about pH 2 to about 1. Specifically, the pH can be adjusted to be optimal for any given active agent by controlling the amount of protonation of the compound. 100841 Protonated forms of the described compounds can be generated by subjecting the purified, partially purified, or crude compounds, to a low pH (e.g., acidic) environment. Purified or crude compounds were protonated with acid, including phosphoric acid, nitric acid, hydrochloric acid, and acetic acid. 18 100851 Lyophilized or dried-down preparations of compounds to be used in bacterial experiments were dissolved in pyrogen-free, sterile, physiological saline (i.e., 0.85% saline), sterile Sigma water, and filtered through a 0.45 micron Gelman filter (or a sterile 0.2 micron pyrogen-free filter). 100861 When suspended in water or saline, the compounds typically exhibited a pH between 1 and 4.5 depending upon the level of protonation/acidification, which is determined by how much acid is used in the acidification process. 100871 Other procedures to prepare protonated compounds known to the skilled artisan are equally contemplated to be within the scope of the invention. Once the compounds of the present invention have been protonated, they may be separated from any undesired components like, for example, excess acid. The skilled artisan would know of many ways to separate the compounds from undesired components, including but not limited to using an H*-cation exchanger (e.g., H-SCX). For example, the compound may be subjected to chromatography following protonation. In one embodiment, the compound is run over a poly(styrene-divinyl benzene) based resin (e.g., Hamilton's PRP-1 or 3 and Polymer Lab's PLRP) following protonation. [0088] The protonated compounds can be used directly, or in a preferred embodiment, processed further to remove any excess acid and salt, e.g., via precipitation, reverse phase chromatography, diafiltration, or gel filtration. The protonated compounds can be concentrated by lyophilization, solvent evaporation, etc. When suspended in water or saline, the acidified compounds of the invention typically exhibit a pH of between 1 and 4.5 depending upon the level of protonation/acidification, which can be determined by how much acid is used in the acidification process. Alternatively, compounds can be protonated by passage over a cation exchange column charged with hydrogen ions. 2. Acid and Nuclease Resistance. 100891 By introducing the modifications such as those described above to the compounds of the invention, the compounds are rendered more acid and nuclease resistant. Percent acid degradation may be determined using analytical HPLC to assess the loss of functional molecules, or by other suitable methods. Acid degradation is generally measured as a function of time. Preferably, the protonated compounds of the invention are also nuclease resistant, which allows these molecules to maintain activity (e.g., pH stability) in an in vivo setting. Percent degradation of the molecules in a setting containing nuclease may be determined by methods known to those skilled in the art, such as mass spectroscopy. Nuclease degradation is generally measured as a function of time. Preferably, a reference compound is employed in determining the extent or rate of acid or nuclease degradation. The compounds of the invention are 10%, 20%, 30%, 40%, 50%, 70%, 90%, 100%, 150%, 200%, 300%, 500%, 750%, or 100% more stable than a reference compound. II. FORMULATIONS, DOSES, AND DOSING REGIMES 100901 The invention further provides pharmaceutical and homeopathic compositions. [00911 A. Pharmaceutical Compositions. As used herein, the term "pharmaceutical composition" refers to a therapeutic composition that is used to treat a particular disease or disorder or symptoms, and that is suitable for systemic, oral, topical or aerosol administration in humans and in animals. The presently described antimicrobial and antiviral compositions may be administered to the body by any suitable means used to administer conventional antibiotics ,antifungals, and antivirals. For example, the compositions may be administered via oral, injection, topical or aerosol routes. 1. Formulations. [00921 The Compositions containing the compounds of the invention in admixture with one or more pharmaceutically acceptable excipients can be prepared according to known techniques. The excipient may take a wide variety of forms 19 depending on the form of preparation desired for administration, e.g. intravenous, oral, topical, transdermal, aerosol ( for topical or inhalation therapy), suppository, parenteral or spinal injection. The excipient may contain any number of carriers. In addition, the composition may contain stabilizers, preservatives, and other ingredients, in any useful amount, providing that they do not significantly adversely affect the ability of the pharmacological compositions to treat the physiological condition. It is well within the skill of one in the art to determine an appropriate mode of administration and to select an appropriate delivery system. a. Topical: Additives in Topical Compositions of the Invention [00931 A variety of topical delivery systems are well known in the art for delivering bioactive compounds to bacteria in an animal. These systems include, but are not limited to topical creams, solutions, suspensions, emulsions, nasal spray, aerosols for inhalation, and suppository administration. The specific topical delivery system used depends on the location of the bacteria, and it is well within the skill of one in the art to determine the location of the bacteria and to select an appropriate delivery system. Similar ranges of topical delivery systems are well known in the art for delivering the compounds of the invention to a site in an animal that is affected by either fungal or viral infections, and equivalently, the appropriate topical delivery system can be determined by one of skill in the art for a specific infection type. Some exemplary systems are described in the following paragraphs. [00941 The protonated compounds of the invention may be used in conjunction with active agents in products such as lotions, creams, and topical solutions. Other compounds may also be added to have additional moisturizing effects and to improve the consistency of the composition. Examples of such compounds include, but are not limited to: cetyl esters wax, stearyl alcohol, cetyl alcohol, glycerin, methyl paraben, propyl paraben, quaternium-15, humectants, volatile methylsiloxane fluids, and polydiorganosiloxane-polyoxyalkylene. See, e.g., U.S. Pat Nos. 5,153,230 and 4,421,769, which are both incorporated herein by reference. If it is desirable for the composition to have additional cleaning effects, chemicals such as sodium lauryl sulfate or a metal salt of a crboxylic acid may be added. [00951 A wide variety of nonvolatile emollients are useful herein, non-limiting examples of which are listed in McCutcheon's, Vol. 2 Functional Materials, North American Edition, (1992), pp. 137-168, which is incorporated herein by reference in its entirety, and CTFA Cosmetic Ingredient Handbook, Second Edition (1992) which lists Skin-Conditioning Agents at pp. 572-575 and Skin Protectants at p. 580, which is also incorporated herein by reference in its entirety. [00961 Among the nonvolatile emollient materials useful herein especially preferred are silicones, hydrocarbons, esters and mixtures thereof. 100971 Examples of silicone emollients include polyalkylsiloxanes, cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes. Suitable commercially available polyalkylsiloxanes include the polydimethylsiloxanes, which are also known as dimethicones, non-limiting examples of which include the VicasilTM series sold by General Electric Company and the Dow CorningTm 200 series sold by Dow Coming Corporation. Commercially available polyalkylsiloxanes include cyclomethicones (Dow ComingTm 244 fluid), Dow Corning T M 344 fluid, Dow ComingTM 245 fluid and Dow Coming T M 345), etc. A suitable commercially available trimethylsiloxysilicate is sold as a mixture with dimethicone as Dow CormingTM 593 fluid. Also useful herein are dimethiconols, which are hydroxy terminated dimethyl silicones. Suitable commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e.g., Dow CorningTM 1401, 1402, and 1403 fluids). Suitable commercially available polyalkylarylsiloxanes SF1075 methylphenyl fluid (sold by General Electric Company) and 556 Cosmetic Grade phenyl trimethicone fluid (sold by Dow Coming Corporation). 20 100981 Hydrocarbons useful herein include straight and branched chain hydrocarbons having from about 10 to about 30 carbon atoms, more preferably from about 12 to about 24 carbon atoms, and most preferably from about 16 to about 22 carbon atoms. Non-limiting examples of these hydrocarbon materials include dodecane, squalane, cholesterol, 5 hydrogenated polyisobutylene, docosane (i.e., a C 22 hydrocarbon), hexadecane, isohexadecane (a commercially available hydrocarbon sold as PermethylTm 101A by Presperse, South Plainsfield, N.J.). Other hydrocarbon materials useful herein include paraffins and mineral oils such as USP light mineral oil (e.g., KlearolTM available from Witco Corp., Melrose Park, Ill.) and USP heavy mineral oil (e.g., Klearol

T

M available from Witco Corp., Melrose Park, Ill). 100991 The compositions of the invention may include propylene glycol. Propylene glycol acts as a surfactant and assists in penetration, contact, and absorption of the active ingredients. Propylene glycol also serves as a preservative. The compositions of the invention may also include a non-ionic surfactant, such as polysorbate. Such a surfactant provides better surface contact of the composition with the vaginal mucosa by further reducing surface tension. [001001 Suppositories are prepared by mining the protonated compounds with a .lipid vehicle such as theobroma oil, cacao butter, glycerin, gelatin, or polyoxyethylene glycols. [00101] Also useful as nonvolatile emollients are esters, including esters of monofunctional and difunctional fatty acids that have been esterified with alcohols and polyols (i.e., alcohols having two or more hydroxy groups). A wide variety of esters are useful herein, with long chain esters of long chain fatty acids being preferred (i.e., C10-40 fatty acids esterified with CIO 40 fatty alcohols). Non-limiting examples of esters useful herein include those selected from the group consisting of diisopropyl adipate, isopropyl myristate, isopropyl palmitate, myristyl propionate, ethylene glycol distearate, 2-ethylhexyl palmitate, isodecyl neopentanoate C 1 2

.

15 alcohols benzoate, di-2-ethylhexyl maleate, ceryl palmitate, myristyl myristate, stearyl stearate, cetyl stearate, behenyl behenrate, and mixtures thereof. [00102] Certain additives, such as aliphatic alcohols, have limited solubility's in aqueous solution. Compositions comprising any of these compounds, optionally may be formulated, with a lipophilic phase, as in emulsions and liposome dispersions and formulations. Liposomal formulations offer distinct advantages in extending circulation time of the compound, permeability of the compounds and in overall efficacy as antibacterials, antifungals, and antivirals . For example, the active agent may be combined with a lipid, cationic lipid, or anionic lipid (which may be preferred for protonated compounds and/or acidic active agents, e.g., salicylic acid). The resulting emulsion or liposomal suspension in conj unction with the pH stabilizing qualities of the compound of the invention can effectively increase the in vivo half-life of the activity of the composition. Examples of suitable anionic lipids for use with compositions of the invention include, but are not limited to, cardiolipin, dimyristoyl, dipalmitoyl, or dioleoyl phosphatidyl choline or phosphatidyl glycerol, palmitoyloleoyl phosphatidyl choline or phosphatidyl glycerol, phosphatidic acid, lysophosphatidic acid, phosphatidyl seine, phosphatidyl inositol, and anionic forms of cholesterol. The use of cationic, anionic, and/or neutral lipid compositions or liposomes is generally described in International Publications Nos. WO 90/14074, WO 91/16024, WO 91/17424, and U.S. Pat No. 4,897,355, herein incorporated by reference. [001031 In one aspect of the invention, the compounds of the invention are incorporated into liposomes. In some embodiments of the invention, neutral lipids, cholesterol, and/or polyethylene glycol (PEG) are utilized in the liposomes. In some embodiments the liposomal composition is composed of partially hydrogenated soy phosphatidylcholine (PHSC), cholesterol, methoxy-terminated PEG (mPEG), and/or distearoyl phosphatidyl ethanolamine (DSPE). In some embodiments the ratio of PHSC:mPEG: DSPE may be in the range of about 40:50:10 w/w% to about 60:30:10 w/w% or to about 60:35:5 21 w/w/o. In some embodiments the percentage of PHSC is in the range of about 40% to about 60w/w% of the total lipid content. In some embodiments the percentage of mPEG is in the range of about 25% to about 45 w/w/o of the total lipid content. In some embodiments the percentage of DSPE is in the range of about 3% to about 15w/w% of the total lipid content. In other embodiments, the liposome formulation comprises of partially hydrogenated soy phosphatidylcholine (PHSC), cholesterol, and methoxy-terminated PEG (mPEG). In some embodiments the ratio of PHSC:cholesterol: mPEG may be in the range of about 40% to about 60w/w/o PHSC, about 30% to about 40w/w/o cholesterol, and about 5% to about lOw/w% mPEG. In some other embodiments, the liposome formulation comprises about 56% PHSC, about 38% cholesterol and about 6% mPEG. The liposomes can be prepared in any method known in the art. In some embodiments, an ethanol injection method is used to produce liposomes for use in compositions of the invention. 1001041 In some embodiments of the invention, the liposomes have a particle size of about 60nm to about 120 nm diameter. In other embodiments of the invention, the liposomes have a particle size of about 75 nm to 110 nm, or about 80 num to about 100 nm. [001051 The ratio of a compound of the invention to lipids in the liposomal composition may be about 1: 9w/w to about 1:3w/w. In some embodiments the ratio of a compound of the invention to lipids in the liposomal composition may be about 1:5w/w to about 1:3w/w. 1001061 For external application to intact skin or for disinfection of nonliving surfaces, an organic solvent or cosolvent such as ethanol or propanol may be employed. Evaporation of the solvent leaves a residue of the antibiotic and protonated compound on the treated surface to inhibit reinfection. [001071 Any of the above described compositions may further be used in transdermal modes of application. b. Aerosol Compositions. [00108] Aerosols (e.g. for intranasal or mucosal administration) can be prepared by dissolving or suspending the protonated compounds and an active agent in a propellant such as ethyl alcohol or in propellant and solvent phases. The pharmaceutical compositions for topical or inhalation therapy will generally contain from about 0.01% by weight (of the protonated compounds) to about 40% by weight, preferably about 0.02% to about 10% by weight, and more preferably about 0.05% to about 5% by weight depending on the particular form employed. c. Oral Compositions. [00109] C. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations ( such as for example, suspensions, elixirs, and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as for example, powders, capsules, and tablets). d. Injectable Compositions. 100110] For administration by injection, preparations may comprise an aqueous solution of a water soluble, or solubilized, and pharmacologically acceptable form of the compound of the invention in an appropriate liquid, e.g., water or saline solution. Injectable suspensions may also be prepared using appropriate liquid carriers, suspending agents, agents for adjusting the isotonicity, preserving agents, and the like. Actual methods for preparing administrable pharmacological compositions and adjustments necessary for administration to mammals will be known or apparent to those skilled in the art. 22 1001111 Particular formulations may be manufactured according to methods well known in the art. Formulations are given in, for example, Remington's Pharmaceutical Sciences and similar reference works. 2. Doses and Dosing Regimes [001121 The presently described compounds may be formulated with a variety of active ingredients and a variety of physiological carrier molecules. The compounds may optionally be complexed with molecules that enhance their ability to enter the target cells. Examples of such molecules include, but are not limited to, carbohydrates, polyamines, amino acids, peptides, lipids, and molecules vital to bacterial growth. [001131 Administration of the composition will introduce the compounds of the invention to the mammal in a diluted amount. Exemplary unit dosages for oral, injectable, aerosol, or topical administration may be more than about 0.01, 0.05, 0.1, 0.5, 1, or 5 mg/kg, and/or less than about 10, 5, 1, 0.5, 0.1, or 0.05 mg/kg. Exemplary unit dosage ranges may be between about 0.01 mg/kg and 10 mg/kg, or between about 0.010 mg/kg and 1.0 mg/kg, or between about 0.10 mg/kg and 1.0 mg/kg. In some embodiments, the compositions of the invention are administered at unit dosages of about 0.01 to about 100 ug per kg of body weight, or about 0.1 to about 100 ug per kg of body weight, or about 0.1 to about 10 ug per kg of body weight, or about I to about 10 ug per kg of body weight, or about I to about 5 ug per kg of body weight. In some embodiments, unit dosages of the composition of the invention are at or below 100 ug per kg of body weight, or at or below 10 ug per kg of body weight, or at or below 1 ug per kg of body weight, or at or below 0.1 ug per kg of body weight, or at or below 0.01 ug per kg of body weight. [00114] When orally administered, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. In some embodiments,, a patient is instructed to orally take two to three dosage units per day. The dosage unit may be placed under the tongue of the patient or simply swallowed for such oral administration. [001151 The pharmaceutical compositions for topical or aerosol form may contain from about 0.001 percent by weight (of the compound of the invention) to about 40 percent by weight, preferably about 0.02 percent to about 10 percent by weight, and more preferably about 0.05 percent to about 5 percent by weight depending on the particular form employed. 1001161 When topically administered, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. [001171 When administered via aerosol, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. [001181 When administered via injection, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. 1001191 B. Homeopathic compositions In some embodiments, the invention provides homeopathic compositions. Homeopathic compositions may be made by methods known in the art. One exemplary method of making a homeopathic composition comprises (i) triturating solid compound of the invention in a 1/9 ratio with lactose to produce a 1X solid and (ii) repeating the process until the desired attenuation is achieved. In a related vein, a method of making a homeopathic 23 composition comprising (i) dissolving 1 part compound of the invention by weight in liquid to produce ten volumes of liquid attenuation labeled 1X and optionally (ii) mixing I ml of the lX attenuation with 9 ml of diluent to produce a lower concentration, is also addressed. 1001201 In some embodiments, the invention includes homeopathic compositions containing compounds of the invention. In one embodiment, tablets for homeopathic use are preferably produced as placebo tablets that are then medicated by dripping or spraying liquid potencies onto the tablets in such a manner as to ensure a coefficient of impregnation of almost 100 percent. The placebo tablets are preferably formed by compression. Pills or granules are preferably spherical in shape, of about 4 millimeters diameter and 3 to 5 centigrams in weight. They are preferably prepared (from pure lactose) and medicated in the same manner as tablets. For example, solid compound of the invention can be triturated (i.e., ground up) in a 1/9 ratio with lactose (1 gram of oligonucleotide+9 grams of lactose) to produce a lX solid. The process is repeated (1 gram of that material plus 9 grams of lactose) until the desired attenuation is achieved. 1001211 For homeopathic compositions, the excipient may contain any number of carriers, and preferably homeopathic carriers, e.g., homeopathic agents that may increase the efficacy of the homeopathic composition or help to alleviate symptoms associated with a physiological condition. For example, compounds can be dissolved in a liquid 1 part by weight to produce a tenfold volume liquid attenuation labeled 1X. To produce lower dilutions 1 ml of the IX attenuation is used (mixed thoroughly) with 9 ml of diluent to produce 2X. This process is repeated until the desired attenuation is achieved. A homeopathic carrier solution such as that described in U.S. Pat. No. 5,603,915 may be used for increasing the efficacy of the homeopathic agent. This carrier solution is sequentially subjected to an alternating current electrical treatment and a direct current electrical treatment, after which additional ingredients such as seawater, brain hormones, and biologically active enzymes are added. The electrical treatment of the carrier, along with the addition of homeopathically active substances, can be used to increase the efficacy of the homeopathic composition. 1001221 Alternatively, an electromagnetic carrier, such as described in U.S. Pat. No. 5,830,140 may be employed. For homeopathic preparations for example, compounds can be dissolved in a liquid 1 part by weight to produce a ten volumes of liquid attenuation labeled lX. To produce lower dilutions 1 ml of the IX attenuation is used (mixed thoroughly) with 9 ml of diluent to produce 2X. This process is repeated until the desired attenuation is achieved. Typical homeopathic unit doses are given in Table 1. Table 1. Homeopathic Dosages of the Compounds of the Invention. Dilution/Potenc pg/kg 2x 50 3x 5 4x 0.5 5x 0.05 6x 0.005 24 100123] When orally administered, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. In some embodiments,, a patient is instructed to orally take two to three dosage units per day. The dosage unit may be placed under the tongue of the patient or simply swallowed for such oral administration. [001241 When topically administered, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. 1001251 When administered via aerosol, one dosage unit may be administered once every 10, 9, 8, 7, 6, 5, 4, 3, 2, or one day, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 times per day until relief is achieved or until the symptoms disappear or are satisfactorily attenuated. In some embodiments, one dosage unit is administered about once to about four times per day. III. Methods of the Invention. A. Therapeutic Use of Compositions Containing Protonated Compounds 1001261 Preferably, animal hosts that may be treated using the compositions of the present invention include, but are not limited to, invertebrates, vertebrates, birds, mammals such as pigs, goats, sheep, cows, dogs, cats, and particularly humans. The presently described compositions are also contemplated to be effective in combating bacterial contamination of laboratory cultures, consumables (food or beverage preparations), medical devices, hospital apparatus, or industrial processes. 1001271 Examples of bacterial organisms against which the methods and compositions of the invention are effective include gram positive bacteria, gram negative bacteria, and acid fast bacteria, and particularly, Staphylococcus. aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Mycobacterium and Escherichia coli. The methods and compositions of the invention are effective against infection by all bacterial organisms, including members of the following genera: Aerococcus, Listeria, Streptomyces, Chlamydia, Lactobacillus, Eubacterium, Arachnid, Mycobacterium, Peptostreptococcus, Staphylococcus, Corynebacterium, Erysipelothrix, Dermatophilus, Rhodococcus, Pseudomonas, Streptococcus, Bacillus, Peptococcus, Pneumococcus, Micrococcus, Neisseria, Klebsiella, Kurthia, Nocardia, Serratia, Rothia, Escherichia, Propionibacterium, Actinomyces, Helicobacter, Enterococcus, Shigella, Vibrio. Clostridium, Salmonella, Yersinia, and Haemophilus. 1001281 A range of fungi or moulds, called dermatophytes, cause fungal infections of the skin. These fungi are parasites on the skin and cause different symptoms in different parts of the body. They are very infectious and are passed from person to person. Although typically these infections are topical, in certain patients (e.g., .imunosuppressed patients) they may occur systemically or in internally. 1001291 Fungal infections that may be treated with the compositions of the present invention include dermatophytosis (Trichophyton, Epidermophyton, and Microsporum), candidiasis (Candida albicans and other Candida species), tinea versicolor (Pityrosporum orbiculare), tinea pedea (Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophytonfloccosum), tinea capitis and ringworm (Trichophyton tonsurans). [00130] Vaginal yeast infections are generally caused by Candida albicans, which, along with a few types of bacteria, are normally present in relatively small numbers in the vaginal area. Sometimes the yeast multiply rapidly and take over, causing candidiasis or monilia. This is often due to a change in the vaginal environment, injury, sexual transmission, HIV 25 infection, etc. Common environmental disruptions that favor yeast include increased pH, increased heat and moisture, allergic reactions, elevated sugar levels, hormonal fluxes, and reductions in the populations of bacteria that are normally present. 1001311 Bactericidal and/or bacteriostatic activity of the compositions including compounds of the invention may be measured using any number of methods available to those skilled in the art. One example of such a method is measurement of antibacterial activity through use of a MIC (minimal inhibitory concentration) test that is recognized to be predictive of in vivo efficacy for the treatment of a bacterial infection with antibiotics. The compositions of the invention display antibacterial activity in this test, even without pretreatment of the bacteria to permeabilize the membrane. 1001321 The invention provides methods of inhibiting the growth of microorganisms by contacting the microorganisms with compositions of the invention in which the active agent is a protonated compound. These methods are effective against infections in vivo, and particularly topical infections. This is demonstrated by test data showing the minimum inhibitory concentrations (MIC) and minimum biocidal concentrations (MBC) of compositions against various pathogenic organisms cultured in vitro under standard conditions. These in vitro tests strongly correlate with in vivo activity, as is evidenced by the widespread use of the MIC and MBC determinations to predict utility of antimicrobial compositions in treatment of infection in animals, including humans. [001331 Particularly striking is the ability of the present compositions comprising a protonated compound of the invention to extend the range of antimicrobial effectiveness against bacteria previously considered unreactive towards certain conventional antibiotics. For example, the protonated compounds of the invention may be especially useful in compositions to treat acne. 1001341 The protonated compounds of the invention, as well as having, antibacterial activity, have activity as antifungals. The protonated compounds are thus useful as active agents for fungal infections such as tinea pedea and candidasis. 1001351 The protonated compounds of the invention, as well as having antibacterial activity, have activity as antivirals. The protonated compounds are thus useful as active agents for viral infections such as herpes simplex. 1001361 Compositions of the invention may be provided as topical disinfectants for sterilization of surfaces such as countertops, surgical instruments, bandages, and skin; as pharmaceutical compositions, including by way of example creams, lotions, ointments, or solutions for external application to skin and mucosal surfaces, including the cornea, dermal cuts and abrasions, bums, and sites of bacterial or fungal infection; as pharmaceutical compositions, including by way of example creams, lotions, ointments, emulsions, liposome dispersions or formulations, suppositories, or solutions, for administration to internal mucosal surfaces such as the oral cavity or vagina to inhibit the growth of bacteria or fungi, including yeasts; and as pharmaceutical compositions such as creams, gels, or ointments for coating indwelling catheters and similar implants which are susceptible to harboring bacterial or fungal infection. 1. Antimicrobials 100137] The protonated compounds of the invention aie useful as stabilizing and/or preservative compounds in topical antibiotic compositions, both prescription (e.g., benzomycin creams) and over-the-counter (e.g., anti-acne medications containing salicylic acid, benzoyl peroxide and the like.) When used in the therapeutic treatment of disease, an appropriate dosage of a composition containing the protonated compounds of the invention and an active ingredient may be determined by any of several well established methodologies. For instance, animal studies are commonly used to determine the maximal 26 tolerable dose, or MTD, of bioactive agent per kilogram weight. In general, at least one of the animal species tested is mammalian. Those skilled in the art regularly extrapolate doses for efficacy and avoiding toxicity to other species, including human. Additionally, therapeutic dosages may also be altered depending upon factors such as the severity of infection, and the size or species of the host. [001381 Where the therapeutic use of the presently described antimicrobial compositions is contemplated, the compositions are preferably administered by a pharmaceutically acceptable topical carrier. Typically, but not necessarily, the preferred formulation for a given antimicrobial composition is dependant on the location in a host where a given infectious organism would be expected to initially invade, or where a given infectious organism would be expected to colonize or concentrate. For example, topical infections are preferably treated or prevented by formulations designed for application to specific body surfaces, e.g., skin, mucous membranes, etc. In such an embodiment, the composition containing the active ingredient and the protonated compound is formulated in a water, ethanol, and propylene glycol base for topical administration. Alternatively, where the targeted pathogen colonizes nasal passages, compositions suitable for intranasal administration can be formulated. 1001391 Given that bacterial and fungal infections are particularly problematic in immuno- compromised individuals, such as patients suffering from acquired immunodeficiency dis sase syndrome (AIDS), HTV-infected individuals, patients undergoing chemotherapy or radiation therapy, or bone marrow transplantation, etc., an additional embodiment of the presently described invention is the use of the presently described antimicrobial protonated compounds as prophylactic agents to prevent and/or treat infection in immuno-corpromised patients. 2. Antivirals [00140] The said compounds are based on the natural ,.tructures of nucleosides that are synthesized via the optimized synthetic routes. The compounds are modified by some substitutions on the sugar and bases with the 5' and/or 3' blockers. The said compounds possess efficient antiviral activities, stability and low toxicity. 100141] Without being limited by mechanism, it is thought that the compounds inhibit virus replication via three possible mechanisms: 1.) termination of the chain extension by :ncorporating the compounds into the DNA or RNA synthesis;2.) inhibition of viral replication by binding to the replication enzymes; or 3.) inhibition of virally induced nucleotide reductases, leading to the imbalance of the cellular pool of nucleos .des. 100142] Viruses that may be treated by compositions of the invention include, but are not limited to, HIV, HSV, CMV, HBV, HCV and influenza virus. B. Conjunctive Therapies 1001431 The protonated compounds can also be used in conjunction with conventional antimicrobial agents in compositions of the invention. The added activity of the active ingredients may provide for a more efficacious composition, and can provide multiple mechanisms by which the microbes are targeted. Pharmaceutical compositions containing the compounds of the invention in admixture with an active agent and a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. [001441 For example, compositions for the treatment ofacne may comprise the protonated compounds of the invention with salicylic acid, benzoyl peroxide, and/or sulfur. These a mounts of these compounds in compositions of the invention can be determined by one skilled in the art, the effective amounts are well documented. See, C. Zouboulis (Editor) Sebaceous Glands, Acne and Related Disorders: Basic and Clinical Research, Clinical Entities and Treatment (1998). Such 27 conjunctive therapy using the protonated compounds of the invention can increase the efficacy of compositions without having to increase the amounts of the agents currently available to consumers, e.g., the amount found in over-the-counter products. Such compositions are preferably aqueous, a.; oil-based compositions may exacerbate the acne condition. 1001451 The protonated compounds are-also useful in general antibiotic creams for external use, e.g., for application to the skin or eye. Again, the protonated compounds can be used as the sole active agent, or may be used in conjunctive therapy with other agents, including but not limited to triclosan, erythromycin, neomycin sulfate and gramicidin, polymixin, gentanicin, clindamycin, and other topical antibiotics. See e.g., Yoshihito Honda (Editor), Topical Application of Antibiotics: Recent Advances in Ophthalmology (1998). and the Physicians Desk Reference (1999). 1001461 OTC antifungal medications that may be additional active ingredients in the compositions of the invention include: Miconazole, Miconazole nitrate, Polynoxylin, Clotrimazole, Sulconazole nitrate, Econazole nitrate, Tolnaftate, Selenium sulphide, Tioconazole Presciptive antifimgals include drugs such as allylamines, azoles, polyene macrolides, flucytosine, pseudomycins and griseofulvin. Exemplary antifungals include Amphotericin B, Fluconazole /Difluian, Flucytosine, Foscarnet, Itraconazole/Sporonex, Ketoconazble/Nitoral, and Nystatin 1. See also Elewski, Cutaneous Fungal Infections, 2nd Edition (1998) and Segal, Pathogenic Yeasts and Yeast Infections (1994), which are both incorporated by reference. [001471 The topical compositions of the invention contain the protonated compounds as described, and may contain any of a number of additives that are themselves active ingredients, such as a retinoic acid, glycolic acid, lactic acid, cL'hydroxy acids, keto-hydroxy acids, citric acid, glucuronic acid, galacturonic acid, glucuronolactone, gluconolactone, a-hydroxy-butyric acid, u-hydroxyisobutyric acid, malic acid, pyruvic acid, -phenyllactic acid, 0-phenylpyruvic acid, saccharic acid, mandelic acid, tartaric acid, tartronic acid, 0-hydroxybutyric acid, vitamin A palmitate (retinyl palmitate) and/or vitamin E acetate (tocopheryl acetate). Each of these is preferably present in an amount from about 0.5 wt % to about 20 wt %. In addition, a UV absorbing or blocking material, such as PABA, may be used. [001481 Additional compositions in which the compound of the invention is efficacious include those found in U.S. Pat. No. 5,652,266, directed to combination of alpha-hydroxy acid, retinoid and salicylic acid; U.S. Pat No. 5,843,998, directed to a composition containing alpha hydroxy acids and carbarmide peroxide, either with or without salicylic acid; U.S. Pat No. 5,153,230, which is directed to a formulation in which the major active ingredient is glycolic acid; 4,464,392, which is directed to a antimicrobial formulations containing glycolic acid derivatives; and U.S. Pat. No. 4,105,782, which describes numerous other similar active agents that may be used in the composition of the invention. [001491 The compositions of the invention may also be used as a carrier material for and/or in combination with other medicines, such as spermicidal agents, anti-viral agents and anti-fungal agents, thereby further broadening the compositions medical efficacy. The composition of the present invention may also include a topical anesthetic such as lidocaine hydrochloride and topical steroids, such as corticosteroid, to provide relief from pain or itching during treatment. C. Cosmetic Use of Protonated Compounds of the Invention [001501 The protonated compounds of the invention my be used in cosmetic products such as lotions, creams, and topical solutions as an antimicrobial preservative. The protonated compounds retard and/or prevent the growth of numerous species of bacteria in a cosmetic formulation, such as in a lotion, and thus may be used as a preservative to prevent and/or retard growth of bacteria in the cosmetic preparation. The prctonated compounds may be used in this capacity with any known cosmetic preparation, provided the composition of the p reparation is sufficiently low in pH to retain protonation of the 28 compound, i.e. 7.0 or below. The protonated compounds are present in an amount sufficient to have an antimicrobial effect, and preferably between 0.25 wt % and 10.0 wt %, more preferably between 0.5 wt %,and 5.0 wt%. 1001511 The cosmetic composition of the invention may also contain any of a number of additives that are active ingredients, such as a glycolic or alpha-hydroxy acids, vitamin A palmitate (retinyl palmitate) and/or vitamin E acetate (tocopheryl acetate). Each of these is preferably present in an amount from about 0.5 wt. % to about 5 wt %. In addition, a UV absorbing or blocking material, such as PABA, may be used. [001521 Other compounds may also be added to have additional moisturizing effects and to improve the consistency of the composition. Examples of such compounds include, but are not limited to: cetyl esters wax, stearyl alcohol, cetyl alcohol, glycerin, methyl paraben, propyl paraben, quaternium- 15, humectants, volatile methylsiloxane fluids, and polydiorganosiloxane-polyoxyalkylene. See, e.g., U.S. Pat Nos. 5,153,230 and 4,421,769, which are both incorporated herein by reference. If it is desirable for the composition to have additional cleaning effects, chemicals such as sodium lauryl sulfate or a metal salt of a carboxylic acid may be added. D. Use of Protonated Compounds in Disinfectants 100153] The protonated compounds of the invention may also find use as disinfectants, and particularly as liquid disinfectant preparations having biostatic or preferably biocidal prcperties. The disinfectant solution contains at least a sufficient amount of protonated compounds of the invention, and may ah o contain other active ingredients with biostatic and/or biocidal properties. For example, the disinfectant may contain protonated compounds of the invention with a suitable concentration of a quaternary ammonium compound such as: dimethylbenzyldodecylammonium chloride, dimethylbenzyl decylammonium chloride, dimethylbenzyl decylammonium bromide, and dimethylbenzylloctylammonium chloride. 1001541 In another example, suitable mic:cobiocidal biguanidine compounds, such as oligohexamethylene biguanide salts and bisbiguanides, can be used. See, e.g., U.S. Pat. No; 5,030,659, which is incorporated herein by reference. Additional biocidal ingredients include aldehydes, phenol derivatives, and halogen phenyl derivatives. See, e.g., U.S. Pat. No. 5,767,054, which is incorporated herein by reference. 3ther compounds with such activity, as will be recognized by those skilled in the art, may also be used in conjunction with the protonated compounds of the invention. [001551 In addition to the described active component i, the disinfectant preparations of the invention may contain other typical components depending on the desired use of the formulation. In particular, an acidifier may be used to keep the pH range of the disinfection solution below 6. Suitable solvents for the protonated compounds and/or the other active ingredients may be employed, and preferably are watei or water miscible organic solvents. Solutions such as these may be readily sprayed using compressed air or any other propellants known by those in the art. By assembling the inactive (e.g., compounds of the invention) and/or other active (e.g., antibiotic) agents into lipid-associated structures, the compositions of the invention may be targeted to specific bacterial cell types by the incorporation of suitable targeting agents (i.e., specific antibodies or receptors) into the lipid complex. [001561 These preparations of the invention are especially suitable for surface disinfection in medically-related environments, such as hospitals, veterinary clinics, dental and medical offices and the like. Use of solutions of the invention in the sterilization of surgical instruments is especially preferred. These preparations are also useful in public areas such as schools, public transport, restaurants, hotels and laundries. The disinfectants also find use in home as sanitizers for toilets, basins, and kitchen areas. 29 1001571 The protonated compounds of the invention may also be used in disinfection solutions for skin. Such compositions contain the protonated compound of the .invention in a solution that is in a vehicle suitable for topical use. The disinfectant may be of the quick-drying variety, in which case it is desirable for the protonated compounds to be in an ethanol base. Such solutions preferably contain an emollient for the skin as well, since the alcohol tends to be extremely drying to skin. Examples of suitable emollients include, but are not limited to: a polyhydric alcohol such as polyethylene glycol, glycerin, diglycerin, propylene glycol, butylene glycol, erythritol. dipropylene glycol, and sorbitol. The amount of emollient may be in the range of 0.1-3.0 w/w/o, and more preferably in the range 0.2-1.5 w/w%. In the case where the content of the emollient is less than 0.1 % (by weight) it may not be very effective, and over 3.0%, the solution may be overly sticky. 1001581 Disinfectant solutions for the skin are especially useful in disinfection of hands following medical treatment or waste management. Disinfection may also be useful in surgical settings, both for the medical staff and to sterilize the area of surgery on the patient. For example, surgical instruments can be coated with the protonated compounds of the invention to provide for a sterile coating prior to surgery. IV. EXAMPLES 1001591 The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject invention, and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperature, concentrations, etc.) but some experimental errors and ceviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade, and pressure is at or near atmospheric. EXAMPLE 1 BACTERIAL GROWTH STUDIES IN A BURN MODEL 1001601 Bum wound infection in mice can be established by subcutaneous or topical administration of the bacteria to the sites of the bum. In order to demonstrate the anti-micrcbial activity of the compounds of the present invention, the ability of such compounds to prevent bum wound infection was s-udied. 1001611 Six-week old BALB/c female mice were obtained from the mouse breeding colony at DRES, with breeding pairs purchased from Charles River Canada Ltd. (St. Constant, Quebec, Canada). The use of animals described in this study was approved by DRES Animal Care Committee. Care and handling of animals described in this study followed guidelines set out the Canadian Council on Animal Care. 1001621 Pseudomonas aeruginosa (Strain Utah 4) was initially cultured on the tripticase soya broth, aliquotted and frozen at -70*C. Prior to use, aliquots were thawed and diluted serially in sterile PBS just prior to administration into animals. To ensure viability and virulence, aliquots of the bacteria were periodically re-amplified in tripticase soya broth and colonies determined on tripticase soya agar plates. [00163] LD 50 values were determined using the method of Reed and Muench (Amer. J. Hyg. (1938) 27:493-497), and were found to be approximately 4 x 108 and 2 x 10I CFUs, respectively, for subcutaneous and topical routes of infection. For establishing the lethal doses of the bacteria for the systemic bum wound infection, groups of mice were anesthetized with ketamine/xylazine mixture (50 mg/kg each, given intramuscularly), their backs were then shaved using a clipper, razor and 30 shaving cream. To induce burn in the back of these an:mals, a brass bar (10 x 10 x 100 mm) was heated in a boiling water for 15 min. The end of the heated bar was then applied on the shaved back of the mice for 45 sec. After a waiting period of 30 min, 50 l of the bacterial inoculum (containing approx. 1 x 108-11 CFU of total bacteria) were then applied subcutaneously into the sites of the burn on the animal back. The mice were then allowed to recover, and were monitored daily for symptoms and deaths. Three days later, the mice were shaved and burns were induced as described above. The inoculum containing the same numbers of bacteria was then topically applied (100 pl) evenly on the sites of the bum, and a custom made "mouse jacket" was then put on the infection site, for at least 2 hrs. These mice; were then monitored daily for symptoms and deaths. These lethal dosages of the P. aeruginosa strain used were found to change during the course of this study due to possible decreases in bacterial viability and virulence during storage. As a result, these values were regularly re checked and adjusted. For all treatment studies, approx. 5 LD 50 of the bacteria were used. The survival pattern of the mice infected with 5 LD 5 0 of the bacteria administered by these two routes of infection was similar. Both routes of administration resulted in eventual death of all mice in the test groups by day 3 post infection. All control unburned animals that received equivalent doses of bacteria by either subcutaneous or topical administration without the bum were asymptomatic and found to be completely resistant to the infection. In the mice :hat received the burn and infection, the LD 50 of the bacteria administered topically was approximately 5-fold highei than the subcutaneous route. Unless otherwise stated, all treatment studies described were carried out using subcutaneous ioute of infection. This route of administration was chosen for subsequent studies as it does not require pretreatment of the mice with cyclophosphamide at 3 days prior to infection, and that it causes a more systemic infection. [001641 Mice treated as described above were provided with Nu-2, Nu-3, Nu-4 and Nu-5 by subcutaneous administration (200 pl of solution of approximately 12 mg/mil), and their survival was compared to control, untreated mice. The results of this study are shown in Table 2. The results indicate that the compounds of the present invention were effective in attenuating the incidence of infection of burn wounds. Table 2 Efficacy Of The Compounds Of The Present Invention In Treating Burn Wound Infection Compound # animals surviving % Survival p Value total# tested (expt vs. control) Nu-2 3/5 60% 0.0184 Nu-3 4/5 80% <0.01 Nu-4 5/5 100% <0.01 Nu-5 4/5 80% <0.01 Control 1/45 2% - EXAMPLE 2 SUBCUTANEOUS TREATMENT WITH A PROTONATED MONOMER 1001651 To determine the effectiveness of protonated compounds for the treatment of burn wound infection, mice were subcutaneously infected with 5 LD 5 0 of P. aeruginosa as described above. Mice were then treated in the following manner. For treatment of systemic infection (infection by subcutaneous injection of the bacteria), mice were treated at 2 and 8 hrs post infection. Three groups of mice were treated with protcnated Nu-3. Group I received a subcutaneous injection of 100 pl 35 mg/ml protonated monomer; Group 2 received a subcutmeous injection of 17.5 mg/ml protonated injection; and group three 31 received no monomer. All (5 out of 5) treated Group 1 animals survived, 2 /5 animals of group 2 survived, and no control animals survived the burn infection. 1001661 The bacterial load was determined using the blood and organs of experimental animals. Blood, spleens, livers and the burnt skins were aseptically removed. The blood (100 pl) was serially diluted in sterile PBS and 100 pl of the diluted blood was plated for growth in tripticase soya agar plates. For the organs, they were homogenized in 2 (spleens and skins) or 5 ml (livers) of sterile PBS using hand-held tissue grinder. The tissue homogenates were serially diluted in sterile PBS, and were then plated for growth in TSA, and the inoculated plates were incubated at 37EC overnight. The number of CFUs was then determined. [001671 The animals receiving 35 mg/ml dosage had no detectable bacterial load in the spleen, liver or blood. Animals receiving the 17.5 mg/ml dosage had a lower bacterial load than the control, untreated animals by an order of magnitude: 1.6 x 104 versus 9 x 102 in spleen and 1.2 x 104 versus 1.9 x 103 in liver (treated versus untreated). [001681 The survival rates of control and treated mice vere compared using the Mann-Whitney unpaired nonparametric one tailed test. These tests were performed using GraphPad Prism software program (version 2.0; Graph PAD Software, Inc., San Diego, CA). Differences were considered statistically significant at p <0.05. [001691 The results of this experiment indicate that the compounds of the present invention were effective for the treatment of burn wound infections. EXAMPLE 3 TREATMENT OF TINEA PEDIS [001701 A 75 year old male with diabetes presented with an acute case of tinea pedis. This infection had been treated with conventional antifungals for a period of over a month with little progress made in clearing up this fungal infection. Treatment of the site of tinea pedis was initiated using a topical solution of Nu-3 at a concentration of 31 A 26 o/ml. Treatment of the area continued once a day for three days. At the end of the three-day period, the infection appeared to be completely eradicated. [001711 The results of this experiment indicate that the compounds of the present invention were effective for the treatment of tinea pedis. EXAMPLE 4 ANTIMICROBIAL ACTIVITY OF COMPOUND Nu-4 [001721 The antimicrobial activity of the compounds of the present invention was further demonstrated by incubating various microorganisms in the presence of Compound Nu-4 of the present invention. For such incubations, a stock solution of Nu-4 (12.7 mM) was diluted using 5 sequential 2-fol: dilutions (0.5 ml of test substance in 0.5 ml of 10% Meuller-Hinto broth ("MHB"). To each well of a 96 well microtiter plate were added 150 pl of MHB, 30 pl of compound dilution, 20 pl of lOX bacteria to give an equivalent of about 106 colony fbrming units ("cfu")/ml. Plates were incubated for 24 hours at appropriate temperature, and then scored for growth (NG = no growth; +, some growth; ++, fair amount of growth; +++, dense growth). The results of this experiment are presented in Table 3 below. 32 Table 3 Antimicrobial Activity of Compound Nu-4 Microbial Growth at Compound Dilution Strain Stock 1 2 3 4 5 Control Stapylococcus aureus ATCC#6538 NG NG NG NG +++ +++ ++ Pseudomonas aeruginosa ATCC#9027 NG NG NG NG +++ +++ +++ Salmonella choleraesuis ATCC#6539 NG NG NG NG NG ++ +++ Escherichia coli ATCC#6539 NG NG NG NG +++ +++ + Salmonella typhimirium hisG46 NG NG NG ++ +++ +++ +++ Bacillus subtilis ATCC#9372 NG NG NG NG +++ +++ +++ Serratia marcessens ATCC# 13880 NG NG NG NG +++ +++ + Stapylococcus aureus ATCC#33592 NG NG NG NG NG ++ (methicillin and gentamycin resistant) N Candida albicans ATCCO1023 1 NG NG ++ +++ +++ +++ + Enterococcusfaecalis ATCC 51575 NG NG NG NG +++ +++ + (high level vancomycin resistant) Enterococcusfaecalis ATCC 51299 NG NG NG NG +++ +++ +++ (low level vancomycin resistant) Stapylococcus aureus SU NG NG NG +++ +++ +++ + (methicillin resistant) 1001731 The results of this experiment indicate that the compounds of the present invention possess broad antimicrobial activity. EXAMPLE 5 ANTIMICROBIAL ACTIVITY OF COMPOUND Nu-5 1001741 The antimicrobial activity of the compounds of the present invention was further demonstrated by incubating various microorganisms in the presence of Compound Nu-5 of the present invention. Such incubations were conducted as described in Example 4, except that a stock solution of Nu-5 (12.7 mM) was employed. Plates were incubated for 24 hours at appropriate temperature, and then scored for growth (NG = no growth; +, some growth; -++, fair amount of growth; +++, dense growth). The results of this experiment are presented in Table 4 below. Table 4 Antimicrobial Activity of Compound Nu-5 Microbial Growth at Co pound Dilution Strain Stock 1 2 3 4 5 Control Stapylococcus aureus ATCC#6538 NG NG NG NG + +++ +++ Pseudomonas aeruginosa ATCC#9027 NG NG NG NG ++ +++ ++ Salmonella choleraesuis ATCC//6539 NG NG NG NG NG +++ ++ Escherichia coli ATCC#6539 NG NG NG NG +++ +++ ++ Salmonella typhimirium hisG46 NG NG NG +++ + +++ +++ Bacillus subtilis ATCC#9372 NG NG NG NG +++ +++ ++ Serratia marcessens ATCC#13880 NG NG NG +++ +++ + Stapylococcus aureus ATCC#33592 NG NG NG NG +++ +++ +++ (methicillin and gentamycin resistant) Candida albicans ATCC#1023 I NG NG NG NG +++ Enterococcusfaecalis ATCC 51575 NG NG NG NG ++ +++ +++ (high level vancomycin resistant) Enterococcusfaecalis ATCC 51299 NG NG NG NG NG +++ +++ (low level vancomycin resistant) Stapylococcus aureus SU NG NG NG NG +++ +++ ++ (methicillin resistant) 33 1001751 The results of this experiment also indicate that the compounds of the present invention possess broad antimicrobial activity. EXAMPLE 6 MIC EXPERIMENTS WITH 3 YEAST ORGANISMS: ANTIMICROBIAL ACTIVITY OF COMPOUNDS Nu-3 AND Nu-5 [001761 The antimicrobial activity of the compounds of the present invention was further demonstrated by incubating three yeast organisms in the presence of Compounds Nu-3 and Nu-5 of the present invention. For such incubations, stock solutions of Nu-3 (54 A 260 /ml) and Nu-5 (12.7 mM) were diluted using 5 sequential 2-fold dilutions (30 pl of test substance in 30 pl of sterile water) for each organism. To each well of a 24 well microtiter plate were added 30 p1 of each compound (dilutions were prepared directly in each well), 20 pl of lOX yeast cells to give an equivalent of about 106 colony forming units ("cfu")/ml and 150 pl of 10% Sabouraud dextrose broth. Plates were incubated for 24 hours at 25 *C with shaking (200 RPM) with additional incubation at room temperature for 24 hours, and then scored for growth (NG = no growth; +, some growth; ++, fair amount of growth; +++, dense growth, ND = not done). The results of this experiment are presented in Table 5 below, and indicate that the compounds of the present invention possess broad antimicrobial activity against both prokaryotes and eukaryotes. Table 5 Anti-Yeast Activity of Compounds Nu-3 and Nu-5 Microbial Growth at Compound Dilution Strain Stock 1 2 3 4 5 Control Compound NU-3 Candida Albicans ATCC#44374 ND NG + +++ |++ +++ +++ Candida Albicans ATCC#44373 ND NG + +++ +++ +++ ++ Saccharomyces pastorianus ATCC#2366 ND j NG NG NG NG +? +++ Compound NU-5 Candida Albicans ATCC#44374 ND NG + ++ I ++ + +++.. Candida Albicans ATCC#44373 ND NG + +++ +++ +++ +++ Saccharomyces pastorianus ATCC#2366 ND NG NG NG ING +? ++ EXAMPLE 7 CHEMICAL SYNTHESIS OF Nu-3 COMPOUND (THYMIDINE 3',5'-BIS-(N-BUTYLPHOSPHATE) 1001771 Thymidine (5.6g) is concentrated from anhydrous acetonitrile to form a solid which is suspended in 85 ml of anhydrous dichloromethane. N-butylcyanoethyl-NN-diisopropylphosphoramidite (12.67 gin) is added to the suspension using dichloromethane to transfer. The suspension is stirred vigorously and tetrazole (3.32 g) is added. The reaction is stirred overnight. The progress of the reaction is monitored by 1.) HPLC using a Zorbax C-8 column and an isocratic mobile phase of 75% acetonitrile in 0.1 M TEAA buffer at p-P.0, a flow rate of 1 ml/min, with detection at 254nM to determine when less than 2% thymidine still remains, with appearance of a product peak at an elution time of 2.4 min. or 2.) 3 'P NMR spectroscopy to determine disappearance of amidite starting material. The reaction is cooled in a salt/ice bath to less than -10 *C. A 5-6 M solution of t-butylhydroperoxide in decane (10ml) is added dropwise from a pressure equalizing funnel. Stirring is continued and the reaction is allowed to come to room temperature. The progress of the reaction is followed by HLPC as above, and completion is observed in 2-3 hrs with the product peak appearing at an elution time of 1.5min. The 34 reaction solution is then washed successively with 5% sodium bisulfite, and saturated sodium chloride solution. The organic layer is separated and dried over anhydrous sodium sulf ate, filtered, and concentrated to remove dichloromethane. The remaining decane containing residual oil is washed witl- diethyl ether, and the upper ethereal layer is carefully decanted away from the lower layer. The residual oil is dissolved in dichloromethane and diethyl ether is added. The oil is allowed to settle for approximately 15 min and the ethereal solvent is decanted. The remaining oil is dried under high vacuum overnight. The oily product is accurately weighed, dissolved in 1Oml of methanol per gm of oil, and 2 equivalents of IN sodium hydroxide is added. Stirring is maintained at room temperature. The hydrolysis reaction is monitored by HPLC as above, the product is observed to elute at 1.2min, and completion is observed within 1-2 hrs. The reaction mixture is concentrated under vacuum, with addition of dry methanol to co-evaporate the residual water away from the product. The resultant gum is triturated with acetonitrile (100ml) and stirred for 1-2 hours until the gum precipitates as a filterable solid. The white solid is filtered, washed with acetonitrile, and dried under vacuum. The purity of the product (>99%) is evaluated by "P and 'H NMR spectroscopy. Synthesis via this method is suitable for grain to kilo scale production. EXAMPLE 8 PROTONATION OF Nu-3 [00178] 0.1 N HCl is added to an aqueous solution of Nu-3 (100-300 A260 units/ml) until the solution has a pH of about 1. After acidification, the solution is passed through an acid-resistant column (Biorad or P4) to remove the residual acid and salt and the eluent is lyophilized. When the lyophilized product is dissolved in water or saline, the Nu-3 solution has a pH in the range of about 1. EXAMPLE 9 PREPARATION OF LIPOSOME ENCAPSULATED Nu-3 1001791 A solution is made using PHSPC, cholesterol, and mPEG-DSPE in a ratio of 56:38:6 w/w with a total lipid concentration of 150mM in ethanol, stirring until complete solution is achieved. This solution is added slowly to a solution of Nu-3 (50mg/ml) in ethanol using vortex mixing, to a final ratio of lipid solution to Nu-3 solution of 1:2 (v/v). The mixture is passed through a membrane under pressure to form liposomes. The resulting liposomal mixture is sonicated for 20 see and cycles through 5 min freeze/ 5 min thaw cycles for a total of four cycles. The liposomal mixture is dialyzed against PBS to remove ethanol, then is passed through a Sepharose column to separate unincorporated drug from the liposomal preparation of Nu-3. The resultant liposomal formulation of Nu-3 yields a particle size of 60-100nm, and a drug to lipid ratio of 1:4w/w. EXAMPLE 10 DETERMINATION OF ANTIBACTERIAL EFFECT OF Nu-3 100180] The efficacy of pulmonary delivery of liposomal Nu-3 is tested by examining the ability to inhibit growth of P. aeruginosa in rats. After anesthetization with Ketamine (90 mg/kg) and Xylazine (10 mg/kg), the rats are infected with 1 x 107 CFU of P. aeruginosa. A liposomal formulation of Nu-3 is administrated to rats intra-tracheally at a dose of 200A 260 units per rat. Fours days later, the rats are sacrificed, and lung tissues are collected and are homogenized in 5 ml PBS. 100 pl of the homogenate is inoculated onto Tryficase Soy Agar and the colonies are counted after 1-2 days incubation at 37 0 C. The results, shown in Table 6, demonstrate the ability of Nu- 3 to inhibit pulmonary bacterial infections compared to a PBS control. 35 Table 6: Antibacterial efficacy of liposomal Nu-3 via pulmonary delivery to rats C olony forming units (CFU) x 104 Rats PBS control Nu-3 treatment 0.78 0.48 2 1.60 0.54 3 20.00 0.86 4 3.10 0.16 5 0.12 0.30 X±SE 5.12±3.8 0.46 ±0.11 EXAMPLE 11 DETERMINATION OF ANTIFUNGAL ACTIVITY OF Nu-3 [001811 The efficacy of Nu-3 is tested against two strai:1s of ftngal species: Candida albicans and Saccharomyces pastorianus, in a 24-well plate with a series of dilutions >f Nu-3. The first concentration utilized is 30 pl of aqueous Nu-3 with an OD of 25 added to each well, administering diluted doses to subsequent wells, as indicated. In each well, 20 PI of fungal solution (approximately 10 fungal cells) and 150 pl of 10% Sabouraud Dextrose medium are added, and are cultured on a rotating culture plate at 25'C. The fungal growth inhibition is recorded after 24 hrs. As shown in Table7, Nu-3 markedly suppresses fungal replication and at some con.-entrations, fungal cells are completely eradicated, as compared to vehicle control. Table 7: In-vitro antifungal efficacy of Nu-3 against C. albincans and S. pastorianus. Growth inhibition at different concentration of Nu-3 Fungal 25 OD 12.5 OD 6.25 OD 3.13 OD 1.56 OD Control C albicans - + ++ +++ +++ + S pastorianus - - - - + + EXAMPLE 12 ANTIBACTERIAL EFFICACY OF Nu-3 IN HUMANS [001821 The efficacy of Nu-3 to inhibit microbial infec ion is evaluated in humans. Nu-3 is administered as an aqueous solution at a concentration of 1g/100ml (2X) topically 2-4 times per day, approximately 1 00d per dose. The evaluation is 36 performed at three days post treatment for acute infection and seven days post treatment for chronic infection, as shown in Table 8. Table 8: Antibacterial efficacy of Nu-3 in humans. Severity Severity after Code Patients Sex Age Diseases before treatment* treatment* 1 L.C. M 41 Oral ulcer 10+ 1-2 2 C.S. F 42 Nose furuncle 9 1 3 J.B. F 52 Local nose infection 5 1 4 J.R. F 13 Acne 4 1 5 D.B. F 51 Urethritis 8 1 6 A.R. F 54 Urethritis 9 4 7 L.B. F 65 Urethritis 7 1 11 K.C. M 67 Diabetes ulcer 10+++ 4 12 D.C. M 59 Infection 10++ 5 13 F.C. M 80 Diabetes ulcer 10+++ 2 14 S.H. F 60 Skin infection 7 1 15 N.M. F 46 Skin infection 10+ 1 16 K.M. F 8 Insect bite infection 5 1 17 T.B. M 55 Infection from puncture 6 1 injury 21 J.M. F 28 Streptococcus 5 1 22 M.F. M 37 Surgical infection 8 1 23 C.G. F 64 Surgical infection 9 1 24 K.F. F 31 Fistula 8 1 25 R.C. F 59 Fistula 10 2 37 26 P.C. F 46 Fistula 9 4 30 B.D. F 17 Acne 10 5 31 Z.M. M 14 Acne 5 2 32 M.R. F 36 Acne 6 1 33 K.Y. F 38 Acne 6 3 34 S.G. M 17 Acne 7 1 35 M.B. F 15 Acne 5 1 36 C.B. F 16 Acne 5 2 37 J.F. F 28 Acne 5 2 38 M.H. F 40 Acne 5 1 39 S.H. F 17 Acne 5 1 45 D.W. F 42 Urethritis 8 1 46 D.T. F 38 Infection from puncture 7 2 injury 47 M.J. F 40 Infection from puncture 10+ 3-4 injury 48 T.L. F 12 Acne 4 2 49 M.L. F 15 Acne 5 1 50 J.B. F 57 Urethritis 7 1 51 E.Y. M 38 Folliculitis 9 2 52 J.V. M 6 Infection 10+ 2 53 D.L. F 32 Acne 4 1 54 K.S. F 17 Acne 10 1-2 55 B.M. M 12 Acne 6 2 38 56 J.C. M 16 Acne 7 1 57 J.W. F 26 Acne 5 1 58 T.A. F 13 Acne 5 1 59 J.H. M 15 Acne 8 2 60 B.R. M 15 Acne 9 3 61 H.D. F 17 Acne 10 3 62 K.M. F 8 Ear infection 7 1 63 P.W. F 43 Ear infection 7 1 64 M.B. F 40 Ear infection 7 1 65 S.M. F 33 Ear infection 5 1 * Degree of severity of the infection: 10: most severe; 1: very mild. EXAMPLE 13 ANTIFUNGAL EFFICACY OF Nu-3 IN HUMANS 100183] Eight patients receive Nu-3 solution three times per day (100 pl of 20 A260 units/ml for each application) for two weeks. At the end of this treatment period the antifungal effect is assessed by clinicians. The results of their evaluation, as shown in Table 9, demonstrate that Nu-3 has strong antifungal effects in humans. Table 9: Antifungal efficacy in-vivo in humans. Code Patients Sex Age Severity before Severity after treatment* treatment* 8 P.C. F 46 9 9 K.G. F 32 5 1 10 W.P. F 51 6 2 18 P.Y. F 61 7 1 19 D.A. M 77 8 1 20 R.C. M 46 7 1 39 28 T.H. F 39 7 1 29 S.L. F 42 8 1 30 S.M. F 32 4 * Degree of severity of the infection: 10: most severe; 1: very mild. EXAMPLE 4 IN-VITRO DETERMINATION OF ANTIVIRAL EFFICACY OF NUBIOTICS Antiviral activities are determined based on the inhibition of cytopathic effect (CPE) (Snoeck R, Sakuma T, Clercy ED, Rosenberg A. Holy. Antimicrob Agents Chemother 1988; 32:1839-1844). HEL cells are seeded in a 96-well plate and 2-4 Cell Culture Infectious Doses (CCID 50 ) of the virus (HIV, HSV or HCMV) are added to each well. After absorption for 2h at 37 'C, un-absorbed virus is removed and 100 pl of medium (MEM+2% calf serum) containing Nu-2, Nu-3, or Nu-5 (highest concentration of 100 A 2 6o units/ml, with subsequent dilutions) is added. The plate is incubated at 37'C for 4-6 days, is fixed with 70% ethanol and is stained with 2.5% Giemse solution for 2h. The plate is washed a further three times with H20 and air-dried. CPE is monitored and recorded under a microscope and the antiviral activity is expressed as EC50 (pg/ml). All tests are in triplicates. EXAMPLE 14 IN-VIVO ANTIVIRAL EFFICACY OF Nu-3 IN HUMANS 1001841 Five patients with HSV infection are treated with liposomal Nu-3 at three sprays per day (100 VI of 20 A260 units/ml solution) for two weeks. The patients are evaluated two weeks at that time and the results are shown in Table 10. Table 10: Anti-viral Efficacy of Nu-3 in humans. Patient Patients Sex Age Diseases Diseases status Disease status post Code pre-treatment* treatment* 40 C.R. M 36 HSV 5 1 41 H.S. F 40 HSV 4 1 42 E.B. F 11 HSV 3 1 43 M.K. M 30 HSV 6-7 40 44 C.W. F 57 HSV 10 1-2 * Degree of severity of the infection: 10: most severe; 1: very mild. 1001851 While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. 41

Claims (34)

1. A liposomal composition comprising the compound of Structure 3A or 3B, 0 OH--P - W w X H H ox H HHH H H H H QA I A OH-- I oz OZ Structure 3A or Structure 3B wherein Q is 0; X and Z are independently CH 3 CH 2 CH 2 CH 2 ~, CH 3 CH 2 CH2~, CH 3 CH2~, HO- CH 2 CH 2 CH 2 CH2, XO- CH 2 CH 2 CH 2 CH2, or YO- CH 2 CH 2 CH 2 CH2j; W is H, purine, a modified analogue of purine, pyrimidine, or a modified analogue of pyrimidine; A is H, alkyl, alkoxy, alkyl(O-alkyl), aryl, alkenyl, alkanol, phenol, or enol; and a lipid and wherein said modified analogue of purine or said modified analogue of pyrimidine is an analogue of purine or pyrimidine that does not form Watson-Crick base pairing with the naturally occurring bases; a single ring heteroaryl structure;. a multiring heteroaryl structure; a partially or totally hydrogenated single or multi-ring structure; a partially oxidized single or multi-ring structure; or 42 100129778 a structure that has a similar electron configuration to purine or pyrimidine.

2. The liposomal composition of claim 1, wherein said modified analog of purine or said modified analog of pyrimidine comprises electron withdrawing or electron donating substituents.

3. The liposomal composition of claim 1 or 2, wherein said modified analog of purine or said modified analog of pyrimidine comprises a substituent that is a halogen group, an alcohol group, a diol group, a phosphorus amide group, or a phosphonic acid group.

4. The liposomal composition of any one of claims I to 3, wherein said modified analog of purine or said modified analog of pyrimidine comprises a structure selected from the group consisting of: uridine, thymidine, 2-aminoadenosine, theobromine, caffeine, theophylline, uric acid, pyridine, pyrazine, triazine, indole, acridine, indazole, phenoxazine, phenazine, phenothiazine, quinoline, isoquinoline, quinazoline, pteridine, caprolactam, and lecuomethylene blue.

5. The liposomal composition of any one of claims I to 4, further comprising one or more excipients.

6. The liposomal composition of any one of claims I to 5, wherein said compound is a protonated compound.

7. The liposomal composition of claim 1 wherein X and Z are independently selected from the group consisting of CH 3 CH 2 CH 2 CH2 and HO-CH 2 CH 2 CH 2 CH2~; W is selected from the group consisting of thymidine and H; and A is selected from the group consisting of H and OCH 3 .

8. The liposomal composition of any one of claims I to 7, comprising one or more of neutral lipids, cholesterol, and polyethylene glycol.

9. The liposomal composition of any one of claims I to 8, wherein the ratio of said lipid to said compound of Formula 1 is about 9:1 w/w% to about 3:1 w/w% or about 1:5 w/w% to about 1:3 w/w%. 43 100129778

10. The liposomal composition of any one of claims I to 9, comprising liposomes having a particle size from about 60nm to about IOnm or from about 80nm to about 100nm.

11. The liposomal composition of any one of claims I to 10, wherein said lipid comprises partially hydrogenated soy phosphatidylcholine, cholesterol, and methoxy-terminated polyethylene glycol.

12. The liposomal composition of claim 11, wherein said liposome composition comprises partially hydrogenated soy phosphatidylcholine, cholesterol, and methoxy-terminated polyethylene glycol in a ratio of about 50 to about 60 w/w%: about 30 to about 40 w/w%: about 5 to about 10 w/w%.

13. The liposomal composition of claim 12, wherein said lipid comprises partially hydrogenated soy phosphatidylcholine, cholesterol, methoxy-terminated polyethylene glycol in a ratio of about 56:38:6 w/w%; and said liposomal composition has a lipid to drug ratio of about 4 to about 1 w/w% and has a liposomal particle size of about 80nm to about 100nm.

14. A compound of Formula 2 Formula 2.

15. A compound of Formula 3 KA K H H /H HCK Formula 3. 44 100129778

16. A compound of Formula 4 % H CH 3 CH 2 CHCH 2 ~ 0 - 0 H H _ H H 1 / 0 HO OcH2C4 Formula 4.

17. A method of treating a mammal suffering from a bacterial infection consisting of administering to said mammal an effective amount of the liposomal composition of any one of claims I to 13.

18. The method of claim 17 wherein said bacterial infection is caused by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Mycobacterium and Escherichia coli, Aerococcus, Listeria, Streptomyces, Chlarnydia, Lactobacillus, Eubacterium, Arachnid, Mycobacterium, Peptostreptococcus, Corynebacterium, Erysipelothrix, Dermatophilus, Rhodococcus, Pseudomonas, Streptococcus, Bacillus, Peptococcus, Pneumococcus, Micrococcus, Neisseria, Klebsiella, Kurthia, Nocardia, Serratia, Rothia, Escherichia, Propionibacterium, Actinomyces, Helicobacter, Enterococcus, Shigella, Vibrio, Clostridium, Salmonella, Yersinia, or Haemophilus.

19. A method of treating a mammal suffering from a fungal infection consisting of administering an effective amount of the liposomal composition of any one of claims I to 13.

20. The method of claim 19, wherein said fungal infection is caused by Trichophyton, Epidermophyton, Microsporum, Candida, Pityrosporum, Trichophyton, or Epidermophyton.

21. A method of treating a mammal suffering from a viral infection consisting of administering an effective amount of the liposomal composition of any one of claims I to 13.

22. The method of claim 21, wherein said viral infection is caused by HIV, HSV, CMV, HBV, HCV or Influenza virus. 45 100129778

23. The method of any one of claims 17-22, wherein the pharmaceutical composition is administered topically.

24. The method of any one of claims 17-22, wherein the pharmaceutical composition is administered orally.

25. The method of any one of claims 17-22, wherein the pharmaceutical composition is administered via aerosol.

26. Use of a composition of any one of claims 1 to 13 in the manufacture of a medicament for treatment of a bacterial infection in a mammal.

27. The use of claim 26, wherein said bacterial infection is caused by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Mycobacterium and Escherichia coli, Aerococcus, Listeria, Streptomyces, Chlarnydia, Lactobacillus, Eubacterium, Arachnid, Mycobacterium, Peptostreptococcus, Corynebacterium, Erysipelothrix, Dermatophilus, Rhodococcus, Pseudomonas, Streptococcus, Bacillus, Peptococcus, Pneumococcus, Micrococcus, Neisseria, Klebsiella, Kurthia, Nocardia, Serratia, Rothia, Escherichia, Propionibacterium, Actinomyces, Helicobacter, Enterococcus, Shigella, Vibrio, Clostridium, Salmonella, Yersinia, or Haemophilus.

28. Use of a composition of any one of claims I to 13 in the manufacture of a medicament for treatment of a fungal infection in a mammal.

29. The use of claim 28, wherein said fungal infection is caused by Trichophyton, Epidermophyton, Microsporum, Candida, Pityrosporum, Trichophyton, or Epidermophyton.

30. Use of a composition of any one of claims I to 13 in the manufacture of a medicament for treatment of a viral infection in a mammal. 46 100129778

31. The use of claim 30, wherein said viral infection is caused by HIV, HSV, CMV, HBV, HCV or Influenza virus.

32. The use of any one of claims 26-31, wherein the medicament is administered topically.

33. The use of any one of claims 26-3 1, wherein the medicament is administered orally.

34. The use of any one of claims 26-3 1, wherein the medicament is administered via aerosol. 47 100129778