Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates
Meenakshi Balganesh,Neela Dinesh,Sreevalli Sharma,Sanjana Kuruppath,Anju V. Nair,Umender Sharma +5 more
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TLDR
It is shown that these four efflux pump KO mutants of M. tuberculosis play a vital role in mediating efflux of different chemical scaffolds and inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis.Abstract:
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.read more
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References
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Mmr, a Mycobacterium tuberculosis Gene Conferring Resistance to Small Cationic Dyes and Inhibitors
TL;DR: Studies of [3H]TPP intracellular accumulation strongly suggest that the resistance mediated by the Mmr protein involves active extrusion of TPP.
Journal ArticleDOI
Assessment of Efflux Pump Gene Expression in a Clinical Isolate Mycobacterium tuberculosis by Real-Time Reverse Transcription PCR
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Journal ArticleDOI
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José A. Aínsa,Esther Pérez,Vladimir Pelicic,François-Xavier Berthet,Brigitte Gicquel,Carlos Martin +5 more
TL;DR: In order to elucidate the role of the aminoglycoside 2′‐N‐acetyltransferase genes in mycobacteria and to determine whether they are silent resistance genes or whether they have a secondary role inMycobacterial metabolism, the aac(2′)‐Id gene from M. smegmatis has been disrupted in the chromosome of M.Smgmatis mc2155.
Journal ArticleDOI
Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria
TL;DR: The combination of trimethoprim with another antibiotic is a well-used combination in anti-infective chemotherapy, and so combination with another agent, such as a quinolone, may be a viable option and further studies are now required.
Journal ArticleDOI
Rv1218c, an ABC Transporter of Mycobacterium tuberculosis with Implications in Drug Discovery
Meenakshi Balganesh,Sanjana Kuruppath,Nimi Marcel,Sreevalli Sharma,Anju V. Nair,Umender Sharma +5 more
TL;DR: Most of the compound classes had significantly better bactericidal activity in the ΔRv 1218c mutant than in the wild-type H37Rv, suggesting the involvement of Rv1218c gene product in effluxing these compounds from M. tuberculosis.