Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions

Catherine Vilchèze, Anthony D. Baughn, Jo Ann A. Tufariello, Lawrence W. Leung, Mack Kuo, Christopher F. Basler, David Alland, James C. Sacchettini, Joel S. Freundlich, William R. Jacobs

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51 Scopus citations

Abstract

Drug resistance in Mycobacterium tuberculosis has become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drug-resistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]). A subset of a chemical library, composed of 300 compounds inhibiting Plasmodium falciparum enoyl reductase, was tested against M. tuberculosis. Four compounds were found to inhibit M. tuberculosis growth with MICs ranging from 1 μM to 10 μM. Testing of these compounds against M. tuberculosis in vitro revealed that only two compounds (CD39 and CD117) were bactericidal against drug-susceptible and drug-resistant M. tuberculosis. These two compounds were also bactericidal against M. tuberculosis incubated under anaerobic conditions. Furthermore, CD39 and CD117 exhibited increased bactericidal activity when used in combination with INH or rifampin, but CD39 was shown to be toxic to eukaryotic cells. The compounds inhibit InhA as well the fatty acid synthase type I, and CD117 was found to also inhibit tuberculostearic acid synthesis. This study provides the TB drug development community with two chemical scaffolds that are suitable for structure-activity relationship study to improve on their cytotoxicities and bactericidal activities in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)3889-3898
Number of pages10
JournalAntimicrobial agents and chemotherapy
Volume55
Issue number8
DOIs
StatePublished - Aug 2011

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    Vilchèze, C., Baughn, A. D., Tufariello, J. A. A., Leung, L. W., Kuo, M., Basler, C. F., Alland, D., Sacchettini, J. C., Freundlich, J. S., & Jacobs, W. R. (2011). Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions. Antimicrobial agents and chemotherapy, 55(8), 3889-3898. https://doi.org/10.1128/AAC.00266-11