Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 13, Pages 5876-5888Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00582
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Funding
- Howard Hughes Foundation
- Roosevelt University
- Chicago State University (CSU) College of Pharmacy
- CSU Center for Teaching and Research Excellence (Faculty Seed Grant)
- Marshall B. Ketchum University College of Pharmacy
- Association Gregory Lemarchal
- Vaincre La Mucoviscidose [RF20130500835]
- Fondation pour la Recherche Medicale (FRM) [DEQ20150331719]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [AIO99534-02]
- NIH/NIAID services [HHSN272201000009I/HHSN27200001 HHSN272201000009I/HHSN27200005]
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Mycobacterium abscessus is a fast-growing, multi drug-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.
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