A piperidinol-containing molecule is active ...
Type de document :
Article dans une revue scientifique
DOI :
URL permanente :
Titre :
A piperidinol-containing molecule is active against Mycobacterium tuberculosis by inhibiting the mycolic acid flippase activity of MmpL3
Auteur(s) :
Dupont, Christian [Auteur]
Chen, Yushu [Auteur]
Xu, Zhujun [Auteur]
Roquet-Banères, Françoise [Auteur]
Blaise, Mickaël [Auteur]
Witt, Anne-Kathrin [Auteur]
Dubar, Faustine [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Guerardel, Yann [Auteur]
Maurer, Florian P. [Auteur]
Chng, Shu-Sin [Auteur]
Kremer, Laurent [Auteur]
Chen, Yushu [Auteur]
Xu, Zhujun [Auteur]
Roquet-Banères, Françoise [Auteur]
Blaise, Mickaël [Auteur]
Witt, Anne-Kathrin [Auteur]
Dubar, Faustine [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Guerardel, Yann [Auteur]
Maurer, Florian P. [Auteur]
Chng, Shu-Sin [Auteur]
Kremer, Laurent [Auteur]
Titre de la revue :
Journal of Biological Chemistry
Nom court de la revue :
J. Biol. Chem.
Numéro :
294
Pagination :
17512-17523
Éditeur :
American Society for Biochemistry & Molecular Biology (ASBMB)
Date de publication :
2019-09-27
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
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 ...
Lire la suite >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.Lire moins >
Lire la suite >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.Lire moins >
Langue :
Anglais
Audience :
Non spécifiée
Projet ANR :
Établissement(s) :
Université de Lille
CNRS
CNRS
Équipe(s) de recherche :
Glycobiologie structurale des interactions hôtes-pathogènes
Date de dépôt :
2020-12-11T13:58:37Z
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