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

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

  • J Med Chem. 2017 Jul 13;60(13):5876-5888. doi: 10.1021/acs.jmedchem.7b00582.
Alan P Kozikowski 1,  Oluseye K Onajole 1 2,  Jozef Stec 3 4,  Christian Dupont 5,  Albertus Viljoen 5,  Matthias Richard 5,  Tridib Chaira 6 7,  Shichun Lun 8,  William Bishai 8,  V Samuel Raj 6,  Diane Ordway 9,  Laurent Kremer 5 10
Affiliations

Affiliations

  • 1 Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.
  • 2 Department of Biological, Chemical and Physical Sciences, Roosevelt University , 425 South Wabash Avenue, Chicago, Illinois 60605, United States.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, Chicago State University , 9501 South King Drive, Chicago, Illinois 60628, United States.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, Marshall B. Ketchum University , 2575 Yorba Linda Boulevard, Fullerton, California 92831, United States.
  • 5 Institut de Recherche en Infectiologie (IRIM), CNRS, UMR 9004, Université de Montpellier , Montpellier Cedex 5 34 293, France.
  • 6 Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR , Rajiv Gandhi Education City, Sonepat 131 029, Haryana India.
  • 7 Daiichi Sankyo India Pharma Private Limited , Sector 18, Gurgaon 122 015, Haryana India.
  • 8 JHU Center for TB Research, Johns Hopkins School of Medicine , 1550 Orleans Street, Baltimore, Maryland 21231-1001, United States.
  • 9 Department of Microbiology, Immunology & Pathology, Mycobacteria Research Laboratory, Colorado State University , Fort Collins, Colorado 80523 United States.
  • 10 IRIM, INSERM , 34293 Montpellier, France.
PMID: 28574259 DOI: 10.1021/acs.jmedchem.7b00582
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.

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