Targeting Mycolic Acid Transport by Indole-2-carboxamides for the Treatment of Mycobacterium abscessus Infections

Alan P. Kozikowski, Oluseye K. Onajole, Jozef Stec, Christian Dupont, Albertus Viljoen, Matthias Richard, Tridib Chaira, Shichun Lun, William Bishai, V. Samuel Raj, Diane Ordway, Laurent Kremer

Research output: Contribution to journalArticlepeer-review

Abstract

Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a clinically significant pathogen in cystic fibrosis (CF) patients. The intrinsic resistance of M. abscessus to most commonly available antibiotics seriously restricts chemotherapeutic options. Herein, we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel of M. abscessus isolates and in infected macrophages. High resistance levels to the indolecarboxamides appear to be associated with an A309P mutation in the mycolic acid transporter MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis remained unaffected, the indolecarboxamides strongly inhibited the transport of trehalose monomycolate, resulting in the loss of trehalose dimycolate production and abrogating mycolylation of arabinogalactan. Our data introduce a hereto unexploited chemical structure class active against M. abscessus infections with promising translational development possibilities for the treatment of CF patients.

Original languageEnglish (US)
Pages (from-to)5876-5888
Number of pages13
JournalJournal of medicinal chemistry
Volume60
Issue number13
DOIs
StatePublished - Jul 13 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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