Title :

A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus

Author(s) :

Dupont, Christian [Auteur]
Viljoen, Albertus [Auteur]
Dubar, Faustine [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Blaise, Mickaël [Auteur]
Bernut, Audrey [Auteur]
Pawlik, Alexandre [Auteur]
Bouchier, Christiane [Auteur]
Brosch, Roland [Auteur]
Guerardel, Yann [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Lelièvre, Joël [Auteur]
Ballell, Lluis [Auteur]
Herrmann, Jean-Louis [Auteur]
Biot, Christophe [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Kremer, Laurent [Auteur]

Journal title :

Molecular Microbiology

Abbreviated title :

Mol. Microbiol.

Volume number :

101

Pages :

515-529

Publication date :

2016-08

ISSN :

1365-2958

English keyword(s) :

Zebrafish
drug resistance mechanism
mycolic acid
therapeutic activity
Mycobacterium abscessus
MmpL3

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

The natural resistance of Mycobacterium abscessus to most commonly available antibiotics seriously limits chemotherapeutic treatment options, which is particularly challenging for cystic fibrosis patients infected with ...
Show more >The natural resistance of Mycobacterium abscessus to most commonly available antibiotics seriously limits chemotherapeutic treatment options, which is particularly challenging for cystic fibrosis patients infected with this rapid-growing mycobacterium. New drugs with novel molecular targets are urgently needed against this emerging pathogen. However, the discovery of such new chemotypes has not been appropriately performed. Here, we demonstrate the utility of a phenotypic screen for bactericidal compounds against M. abscessus using a library of compounds previously validated for activity against M. tuberculosis. We identified a new piperidinol-based molecule, PIPD1, exhibiting potent activity against clinical M. abscessus strains in vitro and in infected macrophages. Treatment of infected zebrafish with PIPD1 correlated with increased embryo survival and decreased bacterial burden. Whole genome analysis of M. abscessus strains resistant to PIPD1 identified several mutations in MAB_4508, encoding a protein homologous to MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis was unaffected, PIPD1 strongly inhibited the transport of trehalose monomycolate, thereby abrogating mycolylation of arabinogalactan. Mapping the mutations conferring resistance to PIPD1 on a MAB_4508 tridimensional homology model defined a potential PIPD1-binding pocket. Our data emphasize a yet unexploited chemical structure class against M. abscessus infections with promising translational development possibilities.Show less >

Language :

Anglais

Administrative institution(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Chemical Glycobiology

Submission date :

2020-02-12T15:11:11Z