A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus.
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.
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.|UMR1173, INSERM, Université de Versailles St Quentin, 2 avenue de la Source de la Bièvre, 78180, Montigny le Bretonneux, France.
Christian
C
Dupont
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.
Albertus
A
Viljoen
Université Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Lille F, 59000, France.
Faustine
F
Dubar
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.
Mickaël
M
Blaise
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.
Audrey
A
Bernut
Institut Pasteur, Unité de Pathogénomique Mycobactérienne Intégrée, 25 rue du Dr. Roux, Paris, 75724, France.
Alexandre
A
Pawlik
Institut Pasteur, PF1 Genopole, 28 rue du Dr. Roux, Paris, 75724, France.
Christiane
C
Bouchier
Institut Pasteur, Unité de Pathogénomique Mycobactérienne Intégrée, 25 rue du Dr. Roux, Paris, 75724, France.
Roland
R
Brosch
Université Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Lille F, 59000, France.
Yann
Y
Guérardel
Diseases of the Developing World, GlaxoSmithKline Tres Cantos, Madrid, 28760, Spain.
Joël
J
Lelièvre
Diseases of the Developing World, GlaxoSmithKline Tres Cantos, Madrid, 28760, Spain.
Lluis
L
Ballell
UMR1173, INSERM, Université de Versailles St Quentin, 2 avenue de la Source de la Bièvre, 78180, Montigny le Bretonneux, France.
Jean-Louis
JL
Herrmann
Université Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, Lille F, 59000, France.
Christophe
C
Biot
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.|INSERM, CPBS, Montpellier, 34293, France.
Laurent
L
Kremer
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001665:Binding Sites; D004195:Disease Models, Animal; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology; D009171:Mycolic Acids / Q000378:metabolism*; D009170:Nontuberculous Mycobacteria / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D015027:Zebrafish
D000995:Antitubercular Agents; D009171:Mycolic Acids; D010880:Piperidines