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
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
Citations
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Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c
Kawaljit Singh,Malkeet Kumar,Malkeet Kumar,Elumalai Pavadai,Elumalai Pavadai,Krupa Naran,Digby F. Warner,Peter G. Ruminski,Kelly Chibale,Kelly Chibale +9 more
TL;DR: Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues.
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Novel adjunctive therapies for the treatment of tuberculosis.
Alvaro A. Ordonez,Mamoudou Maiga,Shashank Gupta,Edward A. Weinstein,William R. Bishai,Sanjay K. Jain +5 more
TL;DR: Significant advances are being made in the development of shorter and effective TB drug regimens and there is growing evidence that host-directed and "non-antimicrobial" pathogen-directed therapies, could serve as novel approaches to enhance TB treatments.
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Mycobacterium tuberculosis Major Facilitator Superfamily Transporters
TL;DR: The structural properties and functions of M. tuberculosis MFS transporters, molecular mechanisms of substrates transfer, and efflux pump inhibitors are summarized for better control of biofilm-associated infections.
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The looming tide of nontuberculous mycobacterial infections in Portugal and Brazil
Daniela Nunes-Costa,Susana Alarico,Margareth Pretti Dalcolmo,Margarida Correia-Neves,Nuno Empadinhas +4 more
TL;DR: The purpose of this review is to bring attention to this emerging health problem in Portugal and Brazil and to emphasize the urgent need for increased surveillance and more comprehensive epidemiological data in both countries, where such information is scarce and seriously thwarts the adoption of proper preventive strategies and therapeutic options.
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Alkaloid extracts from Combretum zeyheri inhibit the growth of Mycobacterium smegmatis
TL;DR: Alkaloid extracts from the leaves of C. zeyheri have potential as a source of lead compounds that may be developed further into antimycobacterial compounds and may be due to inhibition of transport across the cell membrane.
References
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