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Mechanisms of Action: Physiological Effects

Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis

Wei Li, Ashutosh Upadhyay, Fabio L. Fontes, E. Jeffrey North, Yuehong Wang, Debbie C. Crans, Anna E. Grzegorzewicz, Victoria Jones, Scott G. Franzblau, Richard E. Lee, Dean C. Crick, Mary Jackson
Wei Li
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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Ashutosh Upadhyay
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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Fabio L. Fontes
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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E. Jeffrey North
bDepartment of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Yuehong Wang
cInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
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Debbie C. Crans
dDepartment of Chemistry, Colorado State University, Fort Collins, Colorado, USA
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Anna E. Grzegorzewicz
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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Victoria Jones
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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Scott G. Franzblau
cInstitute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
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Richard E. Lee
bDepartment of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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Dean C. Crick
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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Mary Jackson
aMycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado, USA
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DOI: 10.1128/AAC.03229-14
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ABSTRACT

MmpL3, a resistance-nodulation-division (RND) superfamily transporter, has been implicated in the formation of the outer membrane of Mycobacterium tuberculosis; specifically, MmpL3 is required for the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or outer membrane of M. tuberculosis. Recently, seven series of inhibitors identified by whole-cell screening against M. tuberculosis, including the antituberculosis drug candidate SQ109, were shown to abolish MmpL3-mediated TMM export. However, this mode of action was brought into question by the broad-spectrum activities of some of these inhibitors against a variety of bacterial and fungal pathogens that do not synthesize mycolic acids. This observation, coupled with the ability of three of these classes of inhibitors to kill nonreplicating M. tuberculosis bacilli, led us to investigate alternative mechanisms of action. Our results indicate that the inhibitory effects of adamantyl ureas, indolecarboxamides, tetrahydropyrazolopyrimidines, and the 1,5-diarylpyrrole BM212 on the transport activity of MmpL3 in actively replicating M. tuberculosis bacilli are, like that of SQ109, most likely due to their ability to dissipate the transmembrane electrochemical proton gradient. In addition to providing novel insights into the modes of action of compounds reported to inhibit MmpL3, our results provide the first explanation for the large number of pharmacophores that apparently target this essential inner membrane transporter.

FOOTNOTES

    • Received 2 May 2014.
    • Returned for modification 26 May 2014.
    • Accepted 31 July 2014.
    • Accepted manuscript posted online 18 August 2014.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.03229-14.

  • Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis
Wei Li, Ashutosh Upadhyay, Fabio L. Fontes, E. Jeffrey North, Yuehong Wang, Debbie C. Crans, Anna E. Grzegorzewicz, Victoria Jones, Scott G. Franzblau, Richard E. Lee, Dean C. Crick, Mary Jackson
Antimicrobial Agents and Chemotherapy Oct 2014, 58 (11) 6413-6423; DOI: 10.1128/AAC.03229-14

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Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis
Wei Li, Ashutosh Upadhyay, Fabio L. Fontes, E. Jeffrey North, Yuehong Wang, Debbie C. Crans, Anna E. Grzegorzewicz, Victoria Jones, Scott G. Franzblau, Richard E. Lee, Dean C. Crick, Mary Jackson
Antimicrobial Agents and Chemotherapy Oct 2014, 58 (11) 6413-6423; DOI: 10.1128/AAC.03229-14
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