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Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2009 Sep; Vol. 53 (9), pp. 3675-82. Date of Electronic Publication: 2009 Jun 29. - Publication Year :
- 2009
-
Abstract
- Bacterial efflux pumps have traditionally been studied as low-level drug resistance determinants. Recent insights have suggested that efflux systems are often involved with fundamental cellular physiological processes, suggesting that drug extrusion may be a secondary function. In Mycobacterium tuberculosis, little is known about the physiological or drug resistance roles of efflux pumps. Using Mycobacterium bovis BCG as a model system, we showed that deletion of the Rv1410c gene encoding the P55 efflux pump made the strain more susceptible to a range of toxic compounds, including rifampin (rifampicin) and clofazimine, which are first- and second-line antituberculosis drugs. The efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and valinomycin inhibited the P55-determined drug resistance, suggesting the active export of the compounds by use of the transmembrane proton and electrochemical gradients as sources of energy. In addition, the P55 efflux pump mutant was more susceptible to redox compounds and displayed increased intracellular redox potential, suggesting an essential role of the efflux pump in detoxification processes coupled to oxidative balance within the cell. Finally, cells that lacked the p55 gene displayed smaller colony sizes and had a growth defect in liquid culture. This, together with an increased susceptibility to the cell wall-targeting compounds bacitracin and vancomycin, suggested that P55 is needed for proper cell wall assembly and normal growth in vitro. Thus, P55 plays a fundamental role in oxidative stress responses and in vitro cell growth, in addition to contributing to intrinsic antibiotic resistance. Inhibitors of the P55 efflux pump could help to improve current treatments for tuberculosis.
- Subjects :
- Bacterial Proteins antagonists & inhibitors
Bacterial Proteins genetics
Carbonyl Cyanide m-Chlorophenyl Hydrazone pharmacology
Clofazimine pharmacology
Dithiothreitol pharmacology
Drug Resistance, Multiple, Bacterial genetics
Gene Expression Regulation, Bacterial drug effects
Gene Expression Regulation, Bacterial genetics
Glutathione pharmacology
Hydrogen Peroxide pharmacology
Membrane Transport Proteins genetics
Mutation
Mycobacterium tuberculosis genetics
Mycobacterium tuberculosis growth & development
Oligonucleotide Array Sequence Analysis
Rifampin pharmacology
Valinomycin pharmacology
Antitubercular Agents pharmacology
Bacterial Proteins physiology
Drug Resistance, Multiple, Bacterial drug effects
Membrane Transport Proteins physiology
Mycobacterium tuberculosis drug effects
Mycobacterium tuberculosis metabolism
Oxidative Stress
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 53
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 19564371
- Full Text :
- https://doi.org/10.1128/AAC.00550-09