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

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journal contribution
posted on 13.01.2016, 00:00 authored by W. Li, A. Upadhyay, F.L. Fontes, E.J. North, Y. Wang, D.C. Crans, A.E. Grzegorzewicz, V. Jones, S.G. Franzblau
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.

Funding

This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases grants AI063054 and AI049151 and the American Lebanese Syrian Associated Charities (ALSAC). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We are grateful to W. R. Jacobs, Jr. (Albert Einstein College of Medicine, NY, USA) for the kind gift of M. tuberculosis H37Rv mc2 6206, H.

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Publisher Statement

This is a copy of an article published in the Antimicrobial Agents and Chemotherapy © 2014 American Society for Microbiology Publications

Publisher

American Society for Microbiology

issn

0066-4804

Issue date

01/11/2014

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