1. Academic Validation
  2. A piperidinol-containing molecule is active against Mycobacterium tuberculosis by inhibiting the mycolic acid flippase activity of MmpL3

A piperidinol-containing molecule is active against Mycobacterium tuberculosis by inhibiting the mycolic acid flippase activity of MmpL3

  • J Biol Chem. 2019 Nov 15;294(46):17512-17523. doi: 10.1074/jbc.RA119.010135.
Christian Dupont 1 Yushu Chen 2 Zhujun Xu 2 Françoise Roquet-Banères 1 Mickaël Blaise 1 Anne-Kathrin Witt 3 Faustine Dubar 4 Christophe Biot 4 Yann Guérardel 4 Florian P Maurer 3 Shu-Sin Chng 5 Laurent Kremer 6 7
Affiliations

Affiliations

  • 1 Centre National de la Recherche Scientifique UMR9004, Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier, 34293 Montpellier, France.
  • 2 Department of Chemistry, National University of Singapore, Singapore 117543.
  • 3 National Reference Center for Mycobacteria, Research Center Borstel-Leibniz Lung Center, D-23845 Borstel, Germany.
  • 4 University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France.
  • 5 Department of Chemistry, National University of Singapore, Singapore 117543 chmchngs@nus.edu.sg.
  • 6 Centre National de la Recherche Scientifique UMR9004, Institut de Recherche en Infectiologie de Montpellier, Université de Montpellier, 34293 Montpellier, France laurent.kremer@irim.cnrs.fr.
  • 7 INSERM, Institut de Recherche en Infectiologie de Montpellier, 34293 Montpellier, France.
Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a major human pathogen, and current treatment options to combat this disease are under threat because of the emergence of multidrug-resistant and extensively drug-resistant tuberculosis. High-throughput whole-cell screening of an extensive compound library has recently identified a piperidinol-containing molecule, PIPD1, as a potent lead compound against M. tuberculosis Herein, we show that PIPD1 and related analogs exert in vitro bactericidal activity against the M. tuberculosis strain mc26230 and also against a panel of multidrug-resistant and extensively drug-resistant clinical isolates of M. tuberculosis, suggesting that PIPD1's mode of action differs from those of most first- and second-line anti-tubercular drugs. Selection and DNA Sequencing of PIPD1-resistant mycobacterial mutants revealed the presence of single-nucleotide polymorphisms in mmpL3, encoding an inner membrane-associated mycolic acid flippase in M. tuberculosis Results from functional assays with spheroplasts derived from a M. smegmatis strain lacking the endogenous mmpL3 gene but harboring the M. tuberculosis mmpL3 homolog indicated that PIPD1 inhibits the MmpL3-driven translocation of trehalose monomycolate across the inner membrane without altering the proton motive force. Using a predictive structural model of MmpL3 from M. tuberculosis, docking studies revealed a PIPD1-binding cavity recently found to accommodate different inhibitors in M. smegmatis MmpL3. In conclusion, our findings have uncovered bactericidal activity of a new chemical scaffold. Its anti-tubercular activity is mediated by direct inhibition of the flippase activity of MmpL3 rather than by inhibition of the inner membrane proton motive force, significantly advancing our understanding of MmpL3-targeted inhibition in mycobacteria.

Keywords

Flippase; MmpL3; Mycobacterium tuberculosis; PIPD1; Trehalose Monomycolate; antibiotic action; cell wall; drug action; drug resistance; inhibitor; therapeutic activity.

Figures
Products