Field of the Invention

[0001] The field of the invention is antimicrobial compositions and methods.

Background of the Invention [0002] Antibiotic resistance has become an increasingly significant problem and is frequently observed only a few years following introduction of the antibiotic. Indeed, most common bacterial strains with clinical relevance have already developed resistance against one or another antibiotic, however, have retained sensitivity to other antibiotics. Unfortunately, few bacterial strains are now resistant to most common antibiotics and treatment of infections with those strains has become a major public health concern.

[0003] As development of resistance is often a function of frequent prescription, relatively unusual antibiotics have recently gained attention as possible modalities to treat multi-drug resistant bacterial strains. Among various other compounds, unusual antibiotics include those that include boron, which are typically formed by certain fungi (e.g. , by streptomycetes). For example, boromycin (see e.g., U.S. Pat. No. 3,864,479) and aplasmomycin (J Antibiot 1 977 30(9):714-719) are fairly potent antimicrobial agents. Similar to boromycin is tartrolone (J Antibiot 1995 Jan;48( l ):26-30.) and borophycin (J. Org. Chem., 1994, 59 ( 12), pp 3467- 3471 ), which are boron-containing antibiotics that are also produced by certain fungi. A still further known boron-containing compound of synthetic origin with antibacterial activity is a highly fluorinated tris(pyrazolyl)borate (Journal of Inorganic Biochemistry 101 (2007) 1 180— 1 183 ; Journal of Inorganic Biochemistry 100 (2006) 158-160). These and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition or use of that term provided herein, the definition or use of that term provided herein applies and the definition or use of that term in the reference does not apply.

[0004] However, while at least some of the above fungal and synthetic compounds exhibit relatively potent activity, such activity is often specific to certain microbial species or types (e.g., gram negative bacteria). Moreover, boromycin and chemically related compounds are complex macrolide-type molecules that are not easily synthesized. Therefore, the cost of such compounds is often very high. Moreover, most of the above compounds have relatively high toxicity and therefore exhibit a fairly narrow therapeutic window.

[0005] To reduce or even overcome problems associated with developing resistance, caustic silver, silver salts, and silver nitrate solutions can be used to arrest the spread of infection in wounds due to the antimicrobial effect of silver ions. For example, a relatively commonly used compound is silver sulfadiazine for burn victims. Similarly, various other complexed silver compounds have been known to exhibit antimicrobial action including silver cotton and silver alginates (Polym. Adv. Technol. 2007; 18: 620-628). Silver ion compounds tend to exhibit potent antimicrobial activity, and will in almost all cases not lead to resistance in a microorganism. However, most silver ion compositions will eventually produce a redox reaction in the tissue and consequently lead to various adverse effects. To reduce the problem associated with redox reactions, the silver ion release rate may be controlled by a carrier (e.g. , SILVASORB™ (polyacrylate hydrophilic matrix with ionic silver by Medline Industries, Inc.)). However, due to the slower silver release and reduced availability, such compositions may be less active than other dressings.

[0006] Therefore, although numerous antibiotic agents are known in the art, all or almost all of them suffer from various disadvantages. Consequently, there is still a need to provide improved antimicrobial compositions.

Summary of The Invention [0007] The inventive subject matter provides compounds, compositions, and methods that are useful in treatment of microbial infections. Contemplated compositions will most preferably comprise a hydrophobic compound that includes a tetrahedral or trigonal boron-ligand structure, wherein the compound is preferably an internal salt or forms a salt with a cation, most typically with an antimicrobially active cation. Thus, and viewed from a different perspective, contemplated tetrahedral or trigonal boron-ligand structures may be used as a delivery system for various antimicrobially active cations. Most remarkably, at least some of the compounds presented herein will exhibit dual antimicrobial action, which is likely due to the action of the antimicrobially active cation and the antimicrobial action of the hydrophobic compound per se. [0008] In one especially preferred aspect of the inventive subject matter, method of treating a microbial infection comprises a step of administering a compound in a pharmaceutical composition, wherein the compound is preferably hydrophobic and has a structure according to Formula I

[0010] Formula I [0011] wherein Z _\ , Z2, Z3, and Z4 are independently selected from the group consisting of O, S, and NR7; wherein Ri and R2 are independently null, O, S, NRg, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, or optionally substituted alkynyl; m and n are independently an integer between 1 and 3 ; wherein R3, R4, R5, R6, R7, and Rs are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or optionally substituted aryl; wherein Me+ is a metal cation or null where one of Ri, R2, R3, R4, R5, Re, R7, and Rs includes a positively charged substituent (which may then form an internal salt); and with the proviso that where Ri and R2 are null and where Z _\ , Z2, Z3, and Z4 are O, then at least one of R3, R4, R5, and R6 is not H.

[0012] It is further especially preferred that Zi, Z ₂ , Z3, and Z4 in the compounds according to Formula I will be O, and/or that at least one of Rj and R ₂ are null. Similarly, it is preferred that at least one of Ri and R ₂ in such compounds are null, and/or that at least one of R3, R4, R5, and R6 are optionally H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl. Moreover, it is contemplated that at least one of R3, R4, R5, and 6 is covalently coupled to at least another one of R3, R4, R5, and R6. Consequently, mono-, bi-, tri-, and tetradentate ligand structures are especially contemplated. In further especially preferred aspects, Me+ is an antimicrobially active cation (e.g. , Ag+ or a cation comprising a quaternary ammonium ion). [0013] Therefore, particularly preferred compounds will have a structure according to

Formula II

[0014] Formula II

[0015] wherein R3, R4, R5, and R _¾ are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkoxy, or optionally substituted alkyl; and wherein at least one of R3, R4, R5, and R6 has at least 5 carbon atoms.

[0016] Most preferably, compounds according to Formula II will include those in which two of R3, R4, R5, and Re are H, and in which another two of R3, R4, R5, and Re are optionally substituted acyl, each having between 6 and 20 carbon atoms. As preferred compounds will have significant hydrophobicity, R3, R4, R5, and R6 will be selected such that the compound has a solubility in water of less than 10 mg/ml, and more typically less than 1 mg/ml.

[0017] While not limiting to the inventive subject matter, it is typically preferred that the compounds contemplated herein will be formulated into pharmaceutical compositions for treatment of a microbial infection, and most typically a bacterial (e.g., multi-drug resistant Staphylococcus aureus) or viral infection. Moreover, in at least some aspects of the inventive subject matter, contemplated pharmaceutical compositions will be formulated for topical delivery.

[0018] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.

Brief Description of The Drawing

[0019] Figure 1 depicts exemplary compounds according to the inventive subject matter. Detailed Description

[0020] The inventors have discovered that numerous compounds with antimicrobial activity can be prepared in a relatively simple and effective manner, wherein such compounds may exhibit dual antimicrobial action. Most preferably, contemplated antimicrobial compounds will include those in which boron is bound to one or more ligands to so form a trigonal or tetragonal boron-ligand structure that is negatively charged, and wherein the negative charge is compensated with a cation, which is most preferably a cation with antimicrobial activity.

[0021] While not limiting to the inventive subject matter, it is contemplated that the inventive compounds will exhibit significant antimicrobial action that is at least in part attributable to the (most likely sterically strained) trigonal or tetragonal boron ligand, and/or further exhibits additional antimicrobial action that is at least in part attributable to the cation (e.g., Ag+ ion). Thus the antimicrobial effect may be considered a multi-strike effect, possibly having two distinct targets and/or mechanism of action.

Contemplated Compounds

[0022] The inventors generally contemplate compounds, prodrugs, and metabolites thereof, as well as their pharmaceutically acceptable salts, wherein the compounds have a trigonal or tetragonal boron-ligand structure. Most preferably, contemplated compounds are hydrophobic compounds (i. e., have solubility in water at pH 7.0 and 20 °C of less than 10 mg/ml) and will have a negative net charge that is compensated with an antimicrobially active cation. [0023] Therefore, in one aspect of the inventive subject matter contemplated compounds will include antimicrobially active hydrophobic compounds with a tetrahedral or trigonal boron- ligand structure, wherein the compound is an internal salt or forms a salt with a cation. Most typically, the cation has antimicrobial activity (e.g. , silver or includes quaternary ammonium compound). Viewed from a different perspective, contemplated compounds will include a tetrahedral or trigonal boron-ligand structure and a cation having antimicrobial activity. In especially preferred aspects, the tetrahedral boron-ligand structure will include four oxygen atoms, and/or comprise two bidentate ligands, while the cation having antimicrobial activity is preferably a Ag+ ion or a cation with a quaternary ammonium group.

[0024] In one aspect of the inventive subject matter, the antimicrobially active compound has a structure according to Formula I Me+

-Zl Z

*'·, /

B -

R ₂ Z / ₂ \ Z ₃ R ₃

[0026] Formula I

[0027] wherein Zi , Z ₂ , Z3, and Z4 are independently selected from the group consisting of O, Se, S, and NR5; wherein R, , R ₂ , R3, R4, and R ₅ are independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, or optionally substituted aryl; wherein optionally at least one of Ri , R2, R3, R ₄ , and R5 is covalently coupled to another one of Ri, R ₂ , R3, R ₄ , and R5; and wherein Me+ is a metal cation; most preferably, Zi, Z ₂ , Z3, and Z ₄ , and Ri , R ₂ , R3, R ₄ , and R5 are selected such that the compound has a partitioning coefficient of at least 10: 1 in a hexane:water system.

[0028] Further especially preferred compounds may have a structure according to Formula II

[0029] Formula II [0030] wherein Z _\ , Z ₂ , Z3, and Z ₄ are independently selected from the group consisting of O, S, and NR7; wherein Ri and R ₂ are independently null, O, S, NRs, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, or optionally substituted alkynyl; m and n are independently an integer between 1 and 3 ; wherein R3, R ₄ , R ₅ , R6, R7, and R8 are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, or optionally substituted aryl; wherein Me+ is a metal cation or null where one of Ri, R ₂ , R3, R4, R5, Re, R7, and Rg includes a positively charged substituent; and with the proviso that where R] and R ₂ are null and where Zi , Z ₂ , Z3, and Z4 are O, then at least one of R3, R4, R5, and R is not H. It should further be appreciated that R7 and Rs in NR ₇ and NRs could also be a bond such that the N atom is bound in the compound as -N=.

[0031] It is generally preferred that at least one of R3, R4, R5, and R6 has between 3 and 24 carbon atoms and is independently optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, or H, wherein such pattern of substitution advantageously imparts hydrophobicicty into the compound. Moreover, it is generally preferred that in contemplated compounds at least one (and more preferably at least two, or even all of) Zi, Z ₂ , Z3, and Z4 are O, and that m and n are 0 and Ri and R2 are null. In most preferred aspects, R4 and Re are H, and/or Me+ is Ag. Therefore, especially preferred compounds include a tetrahedral boron-ligand structure that comprises an optionally substituted boron-monoacylglycerol diester. [0032] Consequently, especially preferred compounds will have a structure according to Formula III

[0033]

[0034] Formula III

[0035] wherein R ₃ , R4, R ₅ , and R ₆ are independently H, optionally substituted acyl, optionally substituted thioacyl, optionally substituted aminoacyl, optionally substituted alkoxy, or optionally substituted alkyl; and wherein at least one of R3, R4, R5, and R6 has at least 5 carbon atoms. Alternatively, it is also contemplated that two of R3, R4, R5, and R6 in compounds according to Formula III are H, and that another two of R ₃ , R4, R ₅ , and R6 are optionally substituted acyl, each having between 6 and 20 carbon atoms. It is still further preferred that R3, R4, R5, and R6 are selected such that the compound has a solubility in water of less than 10 mg/ml, and most typically less than 1 mg/ml. [0036] In still further contemplated aspects, suitable compounds will also include all known compounds with antibacterial activity that have reactive groups suitable for formation of a trigonal or tetragonal boron ligand structure. Most typically, such reactive groups will be hydroxyl groups and/or thiol groups. For example, particularly preferred naturally occurring compounds include various flavanoid compounds, and especially catechins (e.g., green tea catechin such as epigallocatechin, epicatechin, etc.), numerous 'mycins' (e.g., antibacterial compounds that are produced by fungi, such as bleomycin, streptomycin, etc.), terpenoids, etc. Further contemplated (typically synthetic) compounds include antibiotics that target bacterial cell wall synthesis (e.g., beta-lactam compounds, including penicillin-type antibiotics or cephalosporin-type compounds), that target the cell membrane (e.g., polymixins), or that interfere with essential bacterial enzymes (e.g., quinolones,

sulfonamides, etc.). Additionally, antibiotics targeting bacterial protein synthesis (e.g., aminoglycosides, macrolides, tetracyclines) and cyclic lipopeptides, glycylcyclines, and oxazolidinones are also contemplated. Such compounds are most preferably reacted with a boron-containig compound (e.g., boric acid) to form with one or more reactive groups the corresponding trigonal or tetragonal boron-ligand structure.

[0037] It should be noted that the term "alkyl" as used herein refers to any linear, branched, or cyclic (cycloalkyl) hydrocarbon in which all carbon-carbon bonds are single bonds. The term "substituted alkyl" as used herein refers to any alkyl that further comprises a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -NH ₂ , - OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(0)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH ₃ ⁺ ), halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof. The term "acyl" as used herein refers to any organic radical (e.g., RCO-; RCS- for thioacyl; RCNR'- for aminoacyl) that can be formed by removing a hydroxyl group from the corresponding organic carboxylic acid. The term "alkoxy" as used herein refers to any alkyl (optionally comprising a double or triple bond) with a terminal O radical. For example, CH3CH20 is considered an alkoxy compound under the scope of this definition.

[0038] The terms "alkenyl" as used herein refers to any linear, branched, or cyclic alkyl with at least one carbon-carbon double bond, and the term "substituted alkenyl" as used herein refers to any alkenyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above. Furthermore, the term "alkynyl" as used herein refers to any linear, branched, or cyclic alkyl or alkenyl with at least one carbon- carbon triple bond. The term "substituted alkynyl" as used herein refers to any alkynyl that further comprises a functional group, and particularly contemplated functional groups include those discussed above. As still further used herein, the term "aryl" refers to any aromatic cyclic alkenyl or alkynyl. The term "substituted aryl" as used herein refers to any aryl that further comprises a functional group, and particularly contemplated functional groups include those discussed above. The term "alkaryl" is employed where the aryl is further covalently bound to an alkyl, alkenyl, or alkynyl.

[0039] The term "heteroalkyl" as used herein refers to any linear, branched, or cyclic hydrocarbon comprising at least one bond in which a carbon atom is covalently bound to a non-carbon atom (e.g., nitrogen atom, sulfur atom, phosphorus atom, etc.). Especially preferred heteroalkyls include heterocyclic compound in which a plurality of atoms form a ring via a plurality of covalent bonds, wherein the ring includes at least one atom other than a carbon atom. Particularly contemplated heterocyclic bases include 5- and 6-membered rings with nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine). Further contemplated heterocylces may be fused (i. e., covalently bound) to another ring or heterocycle, and are thus termed "fused heterocycle" as used herein.

Especially contemplated fused heterocycles include a 5-membered ring fused to a 6- membered ring (e.g., purine, pyrrolo[2,3-d]pyrimidine), and a 6-membered ring fused to another 6-membered or higher ring (e.g., pyrido[4,5-d]pyrimidine, benzodiazepine).

[0040] The term "substituted" as used herein also refers to a replacement of a chemical group or substituent (typically H or OH) with a functional group, and particularly contemplated functional groups include nucleophilic (e.g., -N¾, -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(0)OR [with R being any organic radical], C(X)OH [with X being O, S, NR], etc.), polar groups (e.g., -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH ₃ ⁺ ), halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof. Thus, the term "substituent" includes nucleophilic (e.g., -NH ₂ , -OH, -SH, -NC, etc.) and electrophilic groups (e.g., C(0)OR [with R being any organic radical], C(X)OH [with X being O, S, NR], etc.), polar groups (e.g. , -OH), non-polar groups (e.g., aryl, alkyl, alkenyl, alkynyl, etc.), ionic groups (e.g., -NH ₃ ⁺ ), halogens (e.g., -F, -CI), and all chemically reasonable combinations thereof. [0041] It should further be particularly appreciated that contemplated compounds will also include all prodrug forms, wherein the prodrug form may be activated/converted to the active form in one or more than one step, and wherein the activation/conversion of the prodrug into the active form may occur intracellularly or extracellularly (in a single step or multiple steps). Especially contemplated prodrug forms include those that confer a particular specificity towards a infected cell or organ, and exemplary contemplated prodrug forms are described in "Prodrugs" by Kenneth B. Sloan (Marcel Dekker; ISBN: 0824786297), and "Design of Prodrugs" by Hans Bundgaard (ASIN: 044480675X) which are incorporated by reference herein. [0042] Therefore, suitable prodrug forms of contemplated compounds may be formed for various purposes, including reduction of toxicity, increasing specificity towards a particular microorganism, etc. Among various prodrug forms, acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present compounds are preferred. One of ordinary skill in the art will recognize how to readily modify the present compounds to pro- drug forms to facilitate delivery of active compounds to a target site within the host organism or patient. One of ordinary skill in the art will also take advantage of favorable

pharmacokinetic parameters of the pro-drug forms, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound. Contemplated Compositions

[0043] Consequently, pharmaceutical compositions for treatment of a microbial infection are contemplated in which the composition includes one or more of contemplated antimicrobially active compounds and a pharmaceutically acceptable carrier. While numerous routes of administration are deemed suitable, it is generally preferred contemplated compositions are formulated for topical delivery. However, in further contemplated aspects, pharmaceutical compositions presented herein may also be formulated for oral or parenteral delivery.

[0044] Based on the inventors' discovery of antimicrobial activity of compounds presented herein, it is generally contemplated that these compounds are formulated for treatment of various infectious diseases, and particularly for treatment of a microbial infection. As used herein, the term "microbial' refers to viruses, bacteria, fungi, archaea, and protists, wherein these microbial organisms may be found within, and more typically outside a cell of a host that is infected with the microorganism (and especially a human pathogenic microorganism). Therefore, the inventors contemplate that pharmaceutical compositions with contemplated compounds may be effective for the treatment of numerous infectious diseases, and particularly bacterial, fungal, and viral infections. In general, it is therefore contemplated that the compositions according to the inventive subject matter will comprise a therapeutically effective amount of contemplated compounds (or pharmaceutically acceptable salt, hydrate, or prodrug thereof), and a pharmaceutically acceptable carrier.

[0045] For example, in one particularly preferred aspect of the inventive subject matter, the compositions are formulated for treatment of bacterial infection, and most typically a topical bacterial infection, including those common with burn wounds, ulcerative disorders, diabetes, and skin infections with Staphylococcus (and especially multi-drug resistant Staphylococcus aureus [MRSA]). Alternatively, contemplated compositions may also be formulated for treatment of a topical viral infection, a topical infection with a protozoan, or a topical fungal infection. Still further contemplated compositions may be formulated for treatment of various systemic or organ-specific infections {e.g., bacterial or viral encephalitis, sepsis, protozoan infection such as Plasmodium falciparum, etc.).

[0046] Consequently, it is particularly preferred that contemplated compounds are included in a composition that is formulated with one or more non-toxic pharmaceutically acceptable carriers. Thus, it should be appreciated that pharmaceutical compositions according to the inventive subject matter may be administered to humans and other animals using various routes, including orally, rectally, parenteral ly, intraperitoneally, vaginally, or topically.

[0047] Most preferably, contemplated compositions will be formulated for topical delivery and all known topical formulations are deemed suitable for use herein. Among various other formulations, especially preferred topical formulations include creams, lotions, balms, foams, liquids, powders, and pharmaceutically inactive polymeric carriers that allow coating of an area of skin with the carrier that comprises contemplated compounds. Therefore, formulations will typically include oil-in-water emulsions, water-in-oil emulsions, suspensions, hydrophobic carriers (and especially those comprising oils, waxes, and lipids), and liposome formulations. For example, suitable topical formulations are described in "Topical Drug Delivery Formulations" by (Informa HealthCare; ISBN: 082478183X) or in "Cosmetic Formulation of Skin Care Products" by Zoe Diana Draelos and Lauren A. Thaman (Informa HealthCare; ISBN: 0849339685). Furthermore, it should be noted that contemplated topical formulations may administered under occlusion, or may be administered using iontophoretic methods or electroporation.

[0048] In another example, suitable pharmaceutical compositions for injection preferably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, emulsions, or suspensions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, oils, and injectable organic esters (e.g., ethyl oleate). Contemplated compositions may also contain various inactive ingredients, including preservatives, wetting agents, emulsifying agents, and/or dispersing agents. Sterility may be ensured by inclusion of antibacterial and/or antifungal agents (e.g., paraben, phenol sorbic acid, chlorobutanol, etc.). Where appropriate, osmotically active agents may be included (e.g., sugars, sodium chloride, etc.).

[0049] Alternatively, contemplated compositions may be formulated into solid dosage forms for oral administration, and may therefore be capsules, tablets, pills, powders, and granules. In preferred solid dosage forms, contemplated compound are mixed with at least one of a pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate), a filler or extender (e.g., starch, lactose, sucrose, glucose, mannitol, or silicic acid), a binder (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, etc.), a humectant (e.g., glycerol), a disintegrating agent (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, or sodium carbonate), a solution retarding agent (e.g., paraffin), an absorption accelerator (e.g., quaternary ammonium compound), a wetting agents (e.g., cetyl alcohol and glycerol monostearate), and absorbents (e.g., kaolin, or bentonite clay), and a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate).

[0050] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Contemplated compositions may further be formulated to release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Contemplated compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0051] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art (e.g., water, or other solvent, solubilizing agents), emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide), oils (and in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0052] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0053] Compounds according to the inventive subject matter can also be administered in or as part of liposomes, which may be unilamellar, oligolamellar, or polylamellar. Contemplated compositions in liposome form may further contain stabilizers, preservatives, excipients, etc. Preferred lipids for liposome formation include phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[0054] Actual dosage levels of contemplated compounds in pharmaceutical compositions according to the inventive subject matter may be varied to obtain an amount of contemplated compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Thus, the selected dosage level will depend upon various factors, including the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical histoiy of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Generally, dosage levels of about 0.01 mg to about 500 mg, more preferably of about 0.5 mg to about 50 mg of contemplated compound per kilogram of body weight per day are administered (topical or otherwise) to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. , two to four separate doses per day.

[0055] It should still further be appreciated that contemplated pharmaceutical compositions may also include additional pharmaceutically active compounds, and especially contemplated additional pharmaceutically active compounds include antibacterial and antiviral agents, which may act, for example, on cell division, cell wall synthesis, DNA replication, host cell cycle, or bacterial and/or host cell metabolism. Further suitable active agents include immunologically active agents {e.g. , anti-inflammatory agents, immunosuppressants, steroids, or interferons (alpha, beta, or gamma) and fragments thereof. Of course, it should be recognized that additional pharmaceutically active compounds may be included in the same pharmaceutical composition, or may be administered separately, and a person of ordinary skill in the art will readily determine schedule and route of suitable co-administration of the additional pharmaceutically active compounds.

[0056] Thus, contemplated compounds may be administered alone or in combination with other agents for the treatment of various diseases or conditions. Combination therapies according to the present invention comprise the administration of at least one compound of the present invention or a functional derivative thereof and at least one other

pharmaceutically active ingredient. The active ingredient(s) and pharmaceutically active agents may be administered separately or together and when administered separately this may occur simultaneously or separately in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

Contemplated Uses

[0057] The inventors generally contemplate that the compounds and compositions according to the inventive subject matter may be employed for prophylaxis and/or treatment of various diseases, and in fact for all diseases that positively respond to administration of contemplated compounds. However, particularly preferred diseases include microbial infections, and especially bacterial or fungal topical infections. Therefore, a method of treating an infectious disease in a mammal will comprise a step of administering an effective amount of contemplated pharmaceutical compositions, which is preferably used to treat a (e.g. , topical) bacterial infection or a viral infection. In particularly preferred aspects, the bacterial infection is an infection with a multi-drug resistant Staphylococcus aureus.

[0058] For example, where the microbial infection is a viral infection, it is contemplated that the compounds according to the inventive subject matter may be effective against viruses of the poxviridae family (e.g. , cowpox virus, molluscum contagiosum virus), the herpesviridae family (e.g. , simplex virus, herpes virus), the adenoviridae family (e.g. , adenovirus), the papillomaviridae family (e.g. , HPV virus), the hepadnaviridae family (e.g. , HBV virus), the retroviridae family (e.g. , HIV virus), the reoviridae family (e.g. , rotavirus), the

paramyxoviridae family (e.g. , measles or mumps virus), the orthomyxoviridae family (e.g. , influenza virus), the coronaviridae family (e.g., coronavirus, SARS virus), the picornaviridae family (e.g., enterovirus, poliovirus, etc.), and the flaviviridae (e.g. , HCV, west nile virus). Most typically, use against such viruses is by topical and/or oral administration, however, parenteral administration is also deemed appropriate.

[0059] In a further example, where the microbial infection is a bacterial infection, it is contemplated that the compounds according to the inventive subject matter may be effective against gram positive bacteria and/or gram-negative bacteria. Therefore, contemplated bacterial infections include those with various Bacilli (e.g. , Bacillus anthracis), Bordetella pertussis, Borrelia burgdorferi, various Brucelli (e.g., Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, etc ), Campylobacter jejuni, various Chalmydiae (e.g., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis), various clostridial infections (e.g., Clostridium botidinum, Clostridium difficile, Clostridium perfringens,

Clostridium tetani, etc ), Corynebacterium diphteriae, various enterococci (e.g., Enterococcus faecalis, Enterococcus faecum, etc), Escherichia coli, Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes, various mycobacteriae (e.g., Mycobacterium leprae, Mycobacterium tuberculosis, etc.), Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, various staphylococci (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus), and various streptococci (e.g., Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, etc.), Treponema pallidum, Vibrio cholerae, and Yersinia pestis. Most remarkably, contemplated compounds and compositions were even effective against multi-drug resistant Staphylococcus aureus. [0060] Further suitable uses include those in which contemplated compounds and compositions are employed in the treatment or prevention of parasitic infections and infestations, typically with protozoa (e.g., malaria), amoebae, or microsporidiae.

[0061] In yet another aspect of the inventive subject matter, the inventors also contemplate a method of delivering a Ag+ ion to a tissue. Most typically, such methods will include a step of binding the Ag+ ion to a (preferably lipophilic) tetrahedral boron-ligand structure to thereby form an Ag-containing compound, and a further step of administering the (lipophilic) Ag-containing compound to the tissue. Most remarkably, the silver ions in contemplated compounds did not produce visible stains {i. e. , Ag+ reduction to elemental Ag) upon prolonged storage and even topical application to skin. Without wishing to be bound by any theory or hypothesis, it is contemplated that the lipophilic ligand(s) and/or the lipophilic carrier-solvent significantly decreases the one-electron reduction of the Ag+ ion into the elemental metallic Ag°. Such decrease may be a consequence of the low dielectric constant of the whole formulation media (thus inhibiting the acceptance of an electron), since so far Ag ⁺ salts used in medicine have been mainly hydrophilic water soluble and/or dispersible salts. In these known cases, a photochemical reduction takes place, whereupon a photon liberates an electron into a high dielectric constant media which in turn enhances the deposition of elemental silver. While delivery of Ag ⁺ to tissue is especially contemplated herein, it should be noted that numerous other cations and particularly antimicrobial cations may also be delivered via contemplated compounds. For example, suitable antimicrobial cations include Sn2+, and various quaternary ammonium compounds (e.g., 3-(p-nitrophen- oxy-carbonyl)-propyldimethyldodecylammonium bromide, phenoxycarbonylmethyldimethyl- tetradecylammonium bromide, etc., and those disclosed in U.S. Pat. No. 3,882, 166.

Examples and Experiments

[0062] It should generally be appreciated that for the synthetic procedures presented herein, all or almost all of the precursor molecules are commercially available, and that the synthesis of such reagents is therefore not described in detail herein. For example, boron-containing reagents suitable for use herein include boric acid, metallic borates, and various borate esters (e.g., tri-methyl-, tri-ethyl-, or tri-alkyl-borates). Similarly, lipophilic organic reagents for the formation of the boron-ligand structure include mono-O-acyl, mono-O-alkyl, and mono-O- cycloalkyl derivatives of glycerol (wherein the position of the monoacyl, monoalkyl, monocycloalkyl or other substituent may be at the O- l or 0-2 atom of the glycerol moiety). Similarly, suitable alternative lipophilic reagents include acylated or alkylated (e.g., mono-, di-, tri-or higher) derivatives of a polyol (e.g., erythritol, xylitol, sorbitol, mannitol, glycol, polyethylene glycol, branched polyols, etc.) in which the position of the substituent may be variable. However, it is generally preferred that at least two free hydroxyl group will be in positions 1,2- or 1 ,3- with respect to each other. Still further preferred lipophilic reagents include all vicinal 1 ,2- or 1 ,3-diol compounds with at least two lipophilic substituents proximal to the diol-function. Of course, it should be recognized that in all of these lipophilic reagents, the oxygen atom(s) may be replaced with any other suitable heteroatom that is capable of binding binds boron (e.g., nitrogen, sulfur, selenium, etc.) [0063] The general procedure typically comprises a step of heating and mixing the lipophilic reagent(s) with the boron-containing compound(s) for a time sufficient to allow reaction to occur (or better to complete). Most typically the reaction mixture will at such point become homogenous. For example, where boric acid is combined as a powder with monoacyl-O- glycerol as a liquid, the reaction is complete upon disappearance of the solid phase (which may be accompanied by formation of a homogenous liquid phase when constant removal of water vapor is carried out, preferably in vacuum using a cold trap). In general, suitable reaction temperatures and other conditions will depend on the specific reagents; however, temperatures between about 50 to 150 °C are generally sufficient. It should further be appreciated that the reaction can be catalyzed using suitable catalysts. Moreover, it is generally preferred that the organic ligand will be provided in stoichiometric quantities relative to the boron-containing compound, however, may also be in molar excess. Such excess lipophilic reagent may then serve as the lipophilic phase of the future final formulation.

[0064] Exemplary Reaction of Mono-Glycerides with Boric Acid

[0065] Reaction of Glycerol-Mono-Oleate (GMO) with Boric Acid (BA): GMO (7.12 g; 20 mM) and BA (0.620 g; 10 mM) were mixed in a Pyrex glass flask (of a 50 mL volume) in a heating oil bath under stirring. The initially heterogeneous reaction mixture is then constantly stirred and heated. When the temperature reaches 1 10- 130 °C degrees, evolution of water occurs (as steam) and this liberated steam is led over a cooling trap at reduced pressure to condense into a liquid water or ice. The reaction time varies but usually it can take between 1 -2 hours. The initially visible solid boric acid, at the end of the reaction, went completely into solution to form a homogeneous reaction product. To the so formed GMO-Complexed- BA (while still hot at about 120 °C) solid sodium bicarbonate (0.840 g; 10 mM) is added at once and the resulted heterogeneous reaction mixture was further heated and stirred at 120 °C. Carbon dioxide gradually evolved and the reaction was complete in about 1 5 minutes (no further gas evolution) and the mixture becomes again homogeneous. Thereafter, the reaction product can be used as such for creating the suitable lipid formulations, or it can be further treated as follows:

[0066] To the above hot melt of Na-salt of GMO-complexed BA (at about 120 °C), the antibacterial ly active compound Trimethyl Cethyl Ammonium Chloride (3.43 g: 10 mM) is added and the mixture is stirred (or sonicated) until a homogeneous suspension is obtained (solid NaCl in oily Tetralkyl ammonium salt of GMO-Complexed-BA);

[0067] Alternatively, the Na-salt of GMO-complexed BA (from above) is cooled to RT and mixed with about 50 mL of distilled water, and Trimethyl Cethyl Ammonium Chloride (3.43 g: 10 mM) dissolved in about 50 mL of distilled water is added. In formed emulsion solid NaCl is added to saturate water layer. Upon short standing a clear oily layer separated that represents almost pure Tetralkyl ammonium salt of GMO-Complexed-BA.

[0068] Alternatively, before neutralizing complexed boric acid with a base (e.g., NaHCOa), the reaction mixture is treated with a wet freshly prepared Ag20 (prepared according to a standard procedure). Ag-oxide goes into solution and is homogeneously soluble in the lipophilic organic phase. [0069] Exemplary Reaction Of 9, 10-Dihy droxy-Stearic Acid With Boric Acid

[0070] Starting with 9, 10-Dihydroxy-stearic acid (6.32 g; 20 mM) and with BA (0.620 g; 10 mM), the same synthetic protocol is followed as in the exemplary reaction described above. It is noted that one should be careful to add exactly 10 mM of NaHC03 during the procedure since there is an extra carboxyl group that may make a salt if NaHC03 in excess to l OmM. [0071] Figure 1 depicts exemplary compounds BO to B9 made by the above procedure in which Ri, R2, R3 and R ₄ are independently H or saturated alkyls (C I -24), unsaturated alkyls (CI -24), branched saturated alkyls (C I -24), C 1 -C24 alkynyl, C 1 -C24 substituted alkyl, Cl - C24 substituted alkenyl with 1 -6 double bonds, C 1 -C24 substituted alkynyl, branched unsaturated alkyls (C1 -C24), cyclic saturated alkyls (CI -24), amino acids, alkyl esters of amino acids, etc., wherein each of the above may be optionally substituted. Me+ is preferably an inorganic cation (and especially Ag+ or Sn2+), or an organic cation, most preferably with antimicrobial activity (typically comprising a quaternary ammonium group).

[0072] Exemplary Antimicrobial Activity [0073] A Minimum Inhibitory Concentration (MIC) evaluation of selected test products was performed using a modification of the Macrodilution Broth Method outlined in CLSI Document M7-A7, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Seventh Edition. A duplicate series of eleven two-fold dilutions of each test product were prepared using the appropriate nutrient broth medium. Each series of product dilutions was challenged, in duplicate, versus six different microorganism strains. Following incubation, the Minimum Inhibitory Concentrations (MIC) of each product were determined visually and documented.

[0074] The Minimum Inhibitory Concentration (MIC) of Test Product #2, AGFB (Lot Number 1001 -87), was determined to be 1 :64 (6.56 mcg/mL) versus Escherichia coli (ATCC # 1 1229), 1 :32 (13.13 meg /mL) versus Staphylococcus aureus aureus (ATCC #6538), Staphylococcus aureus aureus MRSA (ATCC #700698; MRSA = Methicillin-Resistant Staphylococcus aureus), and Trichophyton mentagrophytes (ATCC #9533), and to be < 1 :8 (52.50 meg /mL) versus Streptococcus pneumoniae (ATCC #6305). The Minimum Inhibitory Concentration was determined to be < 1 :2 (>210.00 meg /mL) versus Candida albicans (ATCC # 10231).

[0075] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B, C . ... and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.