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

Research output: Contribution to journalArticle

88 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)6413-6423
Number of pages11
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Mycobacterium tuberculosis
Mycolic Acids
Bacillus
Periplasm
Membranes
Membrane Transport Proteins
Urea
Protons
Pharmaceutical Preparations
trehalose monomycolate

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. / Li, Wei; Upadhyay, Ashutosh; Fontes, Fabio L.; North, E. Jeffrey; Wang, Yuehong; Crans, Debbie C.; Grzegorzewicz, Anna E.; Jones, Victoria; Franzblau, Scott G.; Lee, Richard E.; Crick, Dean C.; Jackson, Mary.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 11, 01.11.2014, p. 6413-6423.

Research output: Contribution to journalArticle

Li, W, Upadhyay, A, Fontes, FL, North, EJ, Wang, Y, Crans, DC, Grzegorzewicz, AE, Jones, V, Franzblau, SG, Lee, RE, Crick, DC & Jackson, M 2014, 'Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis', Antimicrobial Agents and Chemotherapy, vol. 58, no. 11, pp. 6413-6423. https://doi.org/10.1128/AAC.03229-14
Li, Wei ; Upadhyay, Ashutosh ; Fontes, Fabio L. ; North, E. Jeffrey ; Wang, Yuehong ; Crans, Debbie C. ; Grzegorzewicz, Anna E. ; Jones, Victoria ; Franzblau, Scott G. ; Lee, Richard E. ; Crick, Dean C. ; Jackson, Mary. / Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 11. pp. 6413-6423.
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