Antimicrobial therapy for bacterial infections

Abstract

The disclosure provides a molecular genetic approach of targeted mutagenesis and heterologous expression, coupled with in vitro and in vivo models of bacterial pathogenesis, to demonstrate that the S. aureus pigment is a virulence factor and potential novel target for antimicrobial therapy.

What is claimed is: 
     
         1 . A method for treating, improving on an effective treatment or preventing a microbial infection in a subject; or for preventing, treating or improving on an effective treatment for an antibiotic resistant microbial infection in a subject, comprising:
 (a) providing pharmaceutical composition comprising:   a small molecule carotenogenesis inhibitor that interacts with a microbial carotenoid synthase enzyme and inhibits the production and/or activity of a carotenoid in a microbe or a bacteria,   wherein inhibition of the production and/or activity of the carotenoid in the microbe or the bacteria renders the microbe or bacteria more susceptible to an oxidative damage,   wherein optionally the oxidative damage to the microbe or the bacteria is by a neutrophil or a human neutrophil in vivo,   and optionally targeting or inhibition of the microbial carotenoid by the small molecule carotenogenesis inhibitor comprises inhibiting the synthesis, increasing the degradation or removal, or neutralizing the function of the microbial carotenoid; and   (b) (i) administering to a subject inflicted with a microbial infection or susceptible to a microbial invention a therapeutically effective dose of the pharmaceutical composition, or   (ii) coating or applying the pharmaceutical composition to a device or a catheter, on a device or a catheter, or with a device or a catheter;   thereby treating, improving on an effective treatment, or preventing the microbial infection,   wherein optionally the subject is a human or a non-human animal.   
     
     
         2 . The method of  claim 1 , wherein the microbial infection comprises:
 (a) a bacterial infection;   (b) a gram positive or a gram negative bacterial infection;   (c) a  Staphylococcus  infection, or the bacterial infection is a  Staphylococcus  sp. infection, or a  Staphylococcus aureus  or a  Staphylococcus epidermidis  infection;   (d) an  Escherichia coli  ( E. coli ), a  P. aeruginosa  or a  Salmonella typhimurium  infection;   (e) a  Streptococcus pyogenes  (group A), a  Streptococcus  sp. (viridans group), a  Streptococcus agalactiae  (group B), a  S. bovis , a  Streptococcus  (anaerobic species), a  Streptococcus pneumoniae , an  Enterococcus  sp., a gram-negative cocci, a  Neisseria gonorrhoeae , a  Neisseria meningitidis , a  Branhamella catarrhalis , a  Bacillus anthracis , a  Bacillus subtilis , a  P. acne Corynebacterium  diphtheria, a  Corynebacterium  species, a diptheroid (aerobic or anaerobic), a  Listeria monocytogenes , a  Clostridium tetani , a  Clostridium difficile , an  Enterobacter  species, a  Proteus mirablis , a  Pseudomonas aeruginosa , a  Klebsiella pneumoniae , a  Salmonella , a  Shigella , a  Serratia  or a  Campylobacter jejuni  infection; or   (f) a fungal infection, wherein optionally the fungal infection is an  Aspergillus fumigatus , a  Burkholderia cepacia , a  Serratia marcesens , a  Microsporum canis , a  Microsporum  sp., a  Trichophyton  sp., a  T. rubrum , a  T. mentagrophyte , a yeast, a  Candida albicans , a  C. Tropicalis , a  Candida  species, a  Saccharomyces cerevisiae , a  Torulopsis glabrata , a  Epidermophyton floccosum , a  Malassezia furfur , a  Pityropsporon orbiculare , a  P. ovale , a  Cryptococcus neoformans , an  Aspergillus fumigatus , an  Aspergillus nidulans , an  Aspergillus  sp., a  Zygomycetes , a  Rhizopus , a  Mucor , a  Paracoccidioides brasiliensis , a  Blastomyces dermatitides , a  Histoplasma capsulatum , a  Coccidioides immitis  or a  Sporothrix schenckii  infection.   
     
     
         3 . The method of  claim 1 , wherein the microbe or bacteria are antibiotic resistant, or the microbe or bacteria are methicillin- or vancomycin-resistant strains, or the microbe or bacteria are Methicillin-Resistant  Staphylococcus Aureus  (MRSA). 
     
     
         4 . The method of  claim 1 , wherein the carotenoid is a  Staphylococcus  sp., or a  Staphylococcus aureus  carotenoid. 
     
     
         5 . The method of  claim 1 , wherein the carotenogenesis inhibitor is a mixed function oxidase inhibitor,
 wherein optionally the mixed function oxidase inhibitor comprises: a 2-diethylaminoethyl-2,2-diphenyl-valerate; a 2,4-dichloro-β-phenylphenoxyethylamine; a 2,4-dichloro-6-phenylphenoxyethyldiethylamine; a piperonyl butoxide, or a combination thereof.   
     
     
         6 . The method of  claim 1 , wherein the contacting is in vivo or in vitro, or the contacting is on a surface suspected of having a microbe, or on a surface of a device or a catheter, or applied with a device or catheter. 
     
     
         7 . The method of  claim 6 , wherein the contacting in vivo is by topical administration and the pharmaceutical composition is formulated for topical administration. 
     
     
         8 . The method of  claim 1 , wherein the carotenogenesis inhibitor is administered in combination with at least one antibiotic, and optionally the carotenogenesis inhibitor and antibiotic are administered simultaneously or are administered sequentially. 
     
     
         9 . The method of  claim 8 , wherein the at least one antibiotic comprises:
 (a) an antibiotic belonging to a class selected from the group consisting of aminoglycosides, penicillins, cephalosporins, carbapenems, monobactams, quinolones, tetracyclines, glycopeptides, chloramphenicol, clindamycin, trimethoprim, sulfamethoxazole, nitrofurantoin, rifampin and mupirocin;   (b) an amikacin, gentamicin, kanamycin, netilmicin, t-obramycin, streptomycin, azithromycin, clarithromycin, erythromycin, erythromycin, estolate, ethylsuccinate, gluceptatellactobionate, stearate, penicillin G, penicillin V, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, ampicillin, amoxicillin, ticarcillin, carbenicillin, mezlocillin, azlocillin, piperacillin, cephalothin, cefazolin, cefaclor, cefamandole, cefoxitin, cefuiroxime, cefonicid, cefmetazole, cefotetan, cefprozil, loracarbef, cefetamet, cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefepime, cefixime, cefpodoxime, cefsulodin, i-mipenem, aztreonam, fleroxacin, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, cinoxacin, doxycycline, m-inocycline, tetracycline, vancomycin or a teicoplanin or any combination thereof;   (c) any combination of at least two or more of (a) and/or (b).   
     
     
         10 . A pharmaceutical composition comprising a small molecule carotenogenesis inhibitor and a pharmaceutically acceptable carrier,
 wherein the small molecule carotenogenesis inhibitor interacts with a microbial carotenoid synthase enzyme and inhibits the production and/or activity of a carotenoid in a microbe or a bacteria,   wherein inhibition of the production and/or activity of the carotenoid in the microbe or the bacteria renders the microbe or bacteria more susceptible to an oxidative damage,   wherein optionally the oxidative damage to the microbe or the bacteria is by a neutrophil or a human neutrophil in vivo,   and optionally targeting or inhibition of the microbial carotenoid by the small molecule carotenogenesis inhibitor comprises inhibiting the synthesis, increasing the degradation or removal, or neutralizing the function of the microbial carotenoid.   
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the composition is a lotion, cream, gel, ointment or spray, or the pharmaceutical composition is formulated for parenteral or for topical administration, or the pharmaceutical composition is formulated administration intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, by inhalation, or transdermally. 
     
     
         12 . A device comprising a small molecule carotenogenesis inhibitor,
 wherein the small molecule carotenogenesis inhibitor interacts with a microbial carotenoid synthase enzyme and inhibits the production and/or activity of a carotenoid in a microbe or a bacteria,   wherein inhibition of the production and/or activity of the carotenoid in the microbe or the bacteria renders the microbe or bacteria more susceptible to an oxidative damage,   wherein optionally the oxidative damage to the microbe or the bacteria is by a neutrophil or a human neutrophil in vivo,   and optionally targeting or inhibition of the microbial carotenoid by the small molecule carotenogenesis inhibitor comprises inhibiting the synthesis, increasing the degradation or removal, or neutralizing the function of the microbial carotenoid.   
     
     
         13 . A catheter comprising a small molecule carotenogenesis inhibitor,
 wherein the small molecule carotenogenesis inhibitor interacts with a microbial carotenoid synthase enzyme and inhibits the production and/or activity of a carotenoid in a microbe or a bacteria,   wherein inhibition of the production and/or activity of the carotenoid in the microbe or the bacteria renders the microbe or bacteria more susceptible to an oxidative damage,   wherein optionally the oxidative damage to the microbe or the bacteria is by a neutrophil or a human neutrophil in vivo,   and optionally targeting or inhibition of the microbial carotenoid by the small molecule carotenogenesis inhibitor comprises inhibiting the synthesis, increasing the degradation or removal, or neutralizing the function of the microbial carotenoid.