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Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates
Anju V. Nair
Published in
2012
PMID: 22314527
Volume: 56
   
Issue: 5
Pages: 2643 - 2651
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. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
About the journal
JournalAntimicrobial Agents and Chemotherapy
ISSN00664804
Open AccessYes
Concepts (50)
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    Abc transporter
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    AMIKACIN
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    AZI 219
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    AZI 335
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    AZI 530
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    AZI 533
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    CLOFAZIMINE
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    Ethambutol
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    ETHIDIUM BROMIDE
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    Gentamicin
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    Isoniazid
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    KANAMYCIN
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    PHENYLALANYLARGININE BETA NAPHTHYLAMIDE
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    Rifampicin
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    RV 0849
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    RV 1218C
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    RV 1258C
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    RV 3065
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    SPECTINOMYCIN
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    Streptomycin
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    Tuberculostatic agent
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    Unclassified drug
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    VERAPAMIL
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    Animal cell
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    Antibiotic sensitivity
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    Article
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    Controlled study
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    Minimum inhibitory concentration
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    Multidrug resistance
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    Mycobacterium tuberculosis
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    Nonhuman
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    Priority journal
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    ANTITUBERCULAR AGENTS
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    ATP-BINDING CASSETTE TRANSPORTERS
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    Bacterial proteins
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    Culture media
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    Dipeptides
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    Drug combinations
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    DRUG RESISTANCE, MULTIPLE, BACTERIAL
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    Drug synergism
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    Gene knockout techniques
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    HOMOLOGOUS RECOMBINATION
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    Humans
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    Microbial sensitivity tests
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    Mutation
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    Plasmids
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    PYRAZOLONES
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    Pyrroles
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    TUBERCULOSIS, PULMONARY
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    VERAPAMIL