Display Settings:

Format

Send to:

Choose Destination
Nat Commun. 2013;4:2907. doi: 10.1038/ncomms3907.

Indoleamides are active against drug-resistant Mycobacterium tuberculosis.

Author information

  • 1Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA.
  • 2Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA.
  • 31] Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 531, Chicago, Illinois 60612, USA [2].
  • 41] Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA [2] KwaZulu-Natal Research Institute for Tuberculosis and HIV, 719 Umbilo Road, Durban 4001, South Africa.
  • 51] Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB2 Suite 103, Baltimore, Maryland 21231, USA [2] KwaZulu-Natal Research Institute for Tuberculosis and HIV, 719 Umbilo Road, Durban 4001, South Africa [3] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA.

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.

PMID:
24352433
[PubMed - indexed for MEDLINE]
PMCID:
PMC3909880
Free PMC Article

Images from this publication.See all images (4)Free text

Figure 1
Figure 2
Figure 3
Figure 4
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk