# US 2014/0154302 A1 · Antimicrobial compositions for treating microbial infections

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- Number: US 2014/0154302 A1
- Document ID: US20140154302A1
- Status: Published application
- Kind: A1
- Application number: 13/364,082
- Filed: 2012-02-01
- Published: 2014-06-05
- Earliest claimed: 2006-05-12
- Assignees: University of Illinois at Urbana-Champaign; The Regents of the University of California
- Inventors: Victor NIZET; George Y. LIU; Eric OLDFIELD; Yongcheng SONG
- Web page: https://patentgrep.com/patent/US20140154302A1

## CPC

- A61K 38/14: Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin}
- A61K 31/662: Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 9/098: {Esters of polyphosphoric acids or anhydrides}
- C07F 9/113: with unsaturated acyclic alcohols
- C07F 9/3808: {Acyclic saturated acids which can have further substituents on alkyl}
- C12N 9/1085: {transferring alkyl or aryl groups other than methyl groups (2.5)}
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/4174: Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 2039/522: {avirulent or attenuated}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The disclosure provides compounds and methods to treat a microbial or a bacterial pathogenesis, and demonstrates that the S. aureus pigment is a virulence factor and potential novel target for antimicrobial therapy.

## Claims

### Claim at position 1

1-19. (canceled)

### Claim 20

An antimicrobial pharmaceutical formulation for topical administration comprising:
(a) at least one squalene synthase inhibitor,
(b) at least one antimicrobial; and
(c) a pharmaceutically acceptable carrier,
wherein the at least one squalene synthase inhibitor is or comprises a compound represented by formula I:
wherein:
m is 0, 1, 2 or 3;
n is an integer between 1 and 10 inclusive;
each D and E are each independently selected from the group consisting of. H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
M1, M2, and M3 are each independently selected from the group consisting of metals, ammonium and esters thereof;
R1 is selected from the group consisting of. H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R1 and R2, together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R2 is selected from the group consisting of. H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R2 and R1, together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R2 and R3, together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R3 is selected from the group consisting of. H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R3 and R2, together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R3 and R4, together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R4 is selected from the group consisting of. H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R4 and R3, together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
L1 is —S—, —SO—, —SO2—, —O—, —N(R19)—, or —C(R20)(R21)—; wherein R19, R20 and R21 are each independently selected from the group consisting of. H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
and the antimicrobial pharmaceutical formulation is formulated for topical administration.

### Claim 21 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, further comprising ingredients such that it is formulated as a lotion, cream, gel, ointment or spray.

### Claim 22 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, further comprising a crtN inhibitor, a diphenylamine, a diphenylamine derivative or an analog thereof.

### Claim 23 (depends on 22)

The antimicrobial pharmaceutical formulation of claim 22, wherein the diphenylamine derivative is a diclofenac sodium, a mefenamic acid or a lobenzarit disodium.

### Claim 24 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, further comprising a bisphosphonate.

### Claim 25 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, further comprising at least one third active agent or pharmaceutical.

### Claim 26 (depends on 25)

The antimicrobial pharmaceutical formulation of claim 25, wherein the at least one third active agent or pharmaceutical comprises a crtN inhibitor, a crtM inhibitor, a farnesyl diphosphate synthase inhibitor or any combination thereof.

### Claim 27 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, wherein the or antimicrobial is an antibiotic or an antibacterial agent.

### Claim 28 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, wherein the antibiotic or antimicrobial comprises. an aminoglycoside; a penicillin; a cephalosporin; a carbapenem; a monobactam; a quinolone; a tetracycline; a glycopeptide; a chloramphenicol; a clindamycin; a trimethoprim; a sulfamethoxazole; a nitrofurantoin; a rifampin; a mupirocin; an amikacin; a gentamicin; a kanamycin; a netilmicin; a t-obramycin; a streptomycin; an azithromycin; a clarithromycin; an erythromycin; an erythromycin; an estolate; an ethylsuccinate; a gluceptatellactobionate; a stearate; a penicillin; a penicillin G; a penicillin V; a methicillin; a nafcillin; an oxacillin; a cloxacillin; a dicloxacillin; an ampicillin; an amoxicillin; a ticarcillin; a carbenicillin; a mezlocillin; an azlocillin; a piperacillin; a cephalothin; a cefazolin; a cefaclor; a cefamandole; a cefoxitin; a cefuiroxime; a cefonicid; a cefmetazole; a cefotetan; a cefprozil; a loracarbef; a cefetamet; a cefoperazone; a cefotaxime; a ceftizoxime; a ceftriaxone; a ceftazidime; a cefepime; a cefixime; a cefpodoxime; a cefsulodin; an i-mipenem; an aztreonam; a fleroxacin; a nalidixic acid; a norfloxacin; a ciprofloxacin; an ofloxacin; an enoxacin; a lomefloxacin; a cinoxacin; a doxycycline; an m-inocycline; a tetracycline; a vancomycin; a teicoplanin; or, any combination thereof.

### Claim 29 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, wherein the antibiotic comprises a vancomycin.

### Claim 30 (depends on 16)

The antimicrobial pharmaceutical formulation of claim 16, wherein the squalene synthase inhibitor compound has the formula:

### Claim 31 (depends on 25)

The antimicrobial pharmaceutical formulation of claim 25, wherein the at least one third active agent or pharmaceutical comprises a second squalene synthase inhibitor.

### Claim 32 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, further comprising an inhibitor of a flavohemoglobin;
wherein the flavohemoglobin is selected from the group consisting of a miconozole, an econozole, a clortrimazole, and a ketoconazole.

### Claim 33 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, formulated as a lotion, a cream, or a soap.

### Claim 34 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, formulated as a liposome.

### Claim 35 (depends on 20)

A catheter comprising an antimicrobial pharmaceutical formulation of claim 20.

### Claim 36 (depends on 20)

A lotion comprising an antimicrobial pharmaceutical formulation of claim 20.

### Claim 37 (depends on 20)

A cream comprising an antimicrobial pharmaceutical formulation of claim 20.

### Claim 38 (depends on 20)

A wipe comprising an antimicrobial pharmaceutical formulation of claim 20.

### Claim 39 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, formulated as a sustained-release preparation.

### Claim 40 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, wherein the antimicrobial pharmaceutical formulation is incorporated or contained within a lotion, a cream, a soap or a wipe.

### Claim 41 (depends on 20)

The antimicrobial pharmaceutical formulation of claim 20, wherein the antimicrobial pharmaceutical formulation is incorporated or contained within a liposome.