Methods of reducing microbial resistance to drugs

The instant strategies and compositions represent an improvement in controlling drug resistance in microbes. AcrAB-like efflux pumps are utilized to control resistance to medication, even in highly resistant microbes. Thus, methods of treating infection, methods of screening for inhibitors of AcrAB-like efflux pumps, and ways of improving antimicrobial activity of medication are all supplied. Pharmaceutical composition containing an inhibitor of an AcrAB-like efflux pump and an antimicrobial agent are also supplied.

 

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BACKGROUND

 

 
Different drugs used to inhibit microbial growth act by inhibiting distinct objectives. By way of instance, the fluoroquinolone class of antibiotics act by inhibiting bacterial DNA synthesis. When used in treatment, fluoroquinolones are nicely absorbedorally, are present in respiratory secretions in higher concentrations than in serum and are concentrated within macrophages. Additionally, fluoroquinolones are well tolerated and have an superb safety record in longterm treatment.
 

 
Antibiotic resistance, and in particular resistance to fluoroquinolones, has come to be an issue. Fluoroquinolone resistance in gram negative bacteria is mainly brought on by mutations affecting the target proteins of the medication. In the case offluoroquinolones, these goals are DNA gyrase and topoisomerase IV. Additionally, mutations affecting regulatory genes like marA, soxS or marA can cause fluoroquinolone resistance (Oethinger et al. 1998. J. Antimicrob. Chemother. 41:111). Mar A isa transcriptional activator encoded by the marRAB operon involved in multiple antibiotic resistance (Alekshun et al. (1997) Antimicrob. Agents Chemother. 41, 2067-2075). The marRAB locus confers resistance to tetracycline, chloramphenicol,fluoroquinolones, nalidixic acid, rifampin, penicillin, as well as some other compounds. But, marRAB doesn’t indicate a multidrug efflux system. Instead, it controls the expression of other loci important in directly mediating drug resistance, e.g., ompF,the gene for outer membrane porin, and the acrAB genes to the AcrAB efflux proteins.
 

 
AcrAB is a multidrug efflux pump (Nikaido, H. (1996) J. Bacteriol. 178, 5853-5859; Okusu et al. (1996) J. Bacteriol. 178, 306-308) whose ordinary physiological function is unknown, although it might help out with protection of cells against bile salts inthe mammalian small intestine (Thanassi et al. (1997) J. Bacteriol. 179, 2512-2518). The AcrAB operon is upregulated by MarA (Ma et al. (1995) Mol. Microbiol. 16, 45-55). Mutations at the repressor gene marR cause overexpression of marA (Alekshunet al. (1997). Antimicrob. Agents Chemother. 41, 2067-2075; Cohen et al. (1993) J. Bacteriol. 175, 1484-492); Seoane et al. (1995) J. Bacteriol. 177, 3414-3419). The soxS gene encodes a MarA homolog (Alekshun et al. (1997) Antimicrob. AgentsChemother. 41, 2067-2075; Li et al. (1996) Mol. Microbiol. 20, 937-945; Miller et al. (1996) Mol. Microbiol. 21, 441-448) which also positively regulates acrAB (Ma et al. (1996) Mol. Microbiol. 19, 101-112).
 

 
The AcrAB pump chiefly controls resistance to big, lipophilic agents that have difficulty penetrating porin channels, such as erythromycin, fusidic acid, dyes, and detergents, while leaving microbes susceptible to little antibiotics which candiffuse through the channel, e.g., tetracycline, chloramphenicol, and fluoroquinolones (Nikaido. 1996. J. Bacteriology 178:5853). Recently, the AcrAB pump has been proven to be important in mediating resistance to other medications used to control microbialgrowth, e.g., non-antibiotic agents such as triclosan (FEMS Microbiol. Lett 1998 Sep. 15; 166: 305-9.
 

 
Microbes often become resistant to antibiotics and/or non-antibiotic agents. This can occur by the purchase of genes encoding enzymes that inactivate the brokers, modify the target of the agent, or result in active efflux of their agent.Enzymes that inactivate synthetic antibiotics such as quinolones, sulfonamides, and trimethoprim have yet to be found. In the case of those antibiotics and natural products for which inactivating or altering enzymes have not emerged, resistance usuallyarises by target modifications (Spratt. 1994. Science 264:388). Enhanced approaches for controlling drug resistance in microbes, particularly in microbes that are exceptionally resistant to medication, would be of tremendous benefit.
 

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