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A new piperidinol derivative targeting mycolic acid transport in Mycobacterium abscessus
Author(s) -
Dupont Christian,
Viljoen Albertus,
Dubar Faustine,
Blaise Mickaël,
Bernut Audrey,
Pawlik Alexandre,
Bouchier Christiane,
Brosch Roland,
Guérardel Yann,
Lelièvre Joël,
Ballell Lluis,
Herrmann JeanLouis,
Biot Christophe,
Kremer Laurent
Publication year - 2016
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/mmi.13406
Subject(s) - mycobacterium abscessus , mycolic acid , biology , antimycobacterial , microbiology and biotechnology , mycobacterium , mycobacterium tuberculosis , bacteria , tuberculosis , genetics , medicine , pathology
Summary 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.