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Mol Microbiol. 2016 Aug;101(3):515-29. doi: 10.1111/mmi.13406. Epub 2016 Jun 1.

A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus.

Author information

1
Centre National de la Recherche Scientifique FRE 3689, Centre d'études d'agents Pathogènes et Biotechnologies pour la Santé, Université de Montpellier, 1919 route de Mende, Montpellier, 34293, France.
2
UMR1173, INSERM, Université de Versailles St Quentin, 2 avenue de la Source de la Bièvre, 78180, Montigny le Bretonneux, France.
3
Université Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Lille F, 59000, France.
4
Institut Pasteur, Unité de Pathogénomique Mycobactérienne Intégrée, 25 rue du Dr. Roux, Paris, 75724, France.
5
Institut Pasteur, PF1 Genopole, 28 rue du Dr. Roux, Paris, 75724, France.
6
Diseases of the Developing World, GlaxoSmithKline Tres Cantos, Madrid, 28760, Spain.
7
INSERM, CPBS, Montpellier, 34293, France.

Abstract

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.

PMID:
27121350
DOI:
10.1111/mmi.13406
[Indexed for MEDLINE]
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