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Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates

Balganesh, Meenakshi, Dinesh, Neela, Sharma, Sreevalli, Kuruppath, Sanjana, Nair, Anju V. and Sharma, Umender 2012, Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates, Antimicrobial agents and chemotherapy, vol. 56, no. 5, pp. 2643-2651, doi: 10.1128/AAC.06003-11.

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Title Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates
Author(s) Balganesh, Meenakshi
Dinesh, Neela
Sharma, Sreevalli
Kuruppath, Sanjana
Nair, Anju V.
Sharma, Umender
Journal name Antimicrobial agents and chemotherapy
Volume number 56
Issue number 5
Start page 2643
End page 2651
Total pages 9
Publisher American Society for Microbiology
Place of publication Washington, D. C.
Publication date 2012-05
ISSN 0066-4804
1098-6596
Keyword(s) antitubercular agents
ATP-binding cassette transporters
bacterial proteins
culture media
dipeptides
drug combinations
multiple bacterial drug resistance
drug synergism
gene knockout techniques
homologous recombination
humans
microbial sensitivity tests
mutation
mycobacterium tuberculosis
plasmids
pyrazolones
pyrroles
pulmonary tuberculosis
verapamil
Summary Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms in Mycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil and L-phenylalanyl-L-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded by Rv1218c, and the SMR (small multidrug resistance) class, encoded by Rv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded by Rv0849 and Rv1258c also mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WT M. tuberculosis cells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps of M. tuberculosis play a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization of Rv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.
Language eng
DOI 10.1128/AAC.06003-11
Field of Research 069999 Biological Sciences not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2012, American Society for Microbiology. All Rights Reserved
Persistent URL http://hdl.handle.net/10536/DRO/DU:30046873

Document type: Journal Article
Collection: Centre for Biotechnology and Interdisciplinary Sciences (BioDeakin)
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