Indoleamides are active against drug-resistant mycobacterium tuberculosis

Shichun Lun, Haidan Guo, Oluseye K. Onajole, Marco Pieroni, Hendra Gunosewoyo, Gang Chen, Suresh K. Tipparaju, Nicole C. Ammerman, Alan P. Kozikowski, William R. Bishai

Research output: Contribution to journalArticlepeer-review

Abstract

Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug-and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3, which confers high resistance to the indoleamide class while remaining susceptible to currently used first-and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent antimycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis.

Original languageEnglish (US)
Article number2907
JournalNature communications
Volume4
DOIs
StatePublished - Dec 19 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Indoleamides are active against drug-resistant mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this