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 (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Guerardel, Yann [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
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 (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Guerardel, Yann [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
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
Mot(s)-clé(s) en anglais :
Mycobacterium tuberculosis
drug action
drug resistance
inhibitor
cell wall
antibiotic action
Flippase
MmpL3
PIPD1
therapeutic activity
Trehalose Monomycolate
drug action
drug resistance
inhibitor
cell wall
antibiotic action
Flippase
MmpL3
PIPD1
therapeutic activity
Trehalose Monomycolate
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique
Chimie/Chimie théorique et/ou physique
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
Comité de lecture :
Oui
Audience :
Internationale
Vulgarisation :
Non
Projet ANR :
Établissement(s) :
Université de Lille
CNRS
CNRS
Équipe(s) de recherche :
Chemical Glycobiology
Date de dépôt :
2020-12-11T13:58:37Z
2020-12-16T14:03:22Z
2020-12-16T14:03:22Z
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