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

Antimicrobial Agents and Chemotherapy
Catherine VilchèzeWilliam R Jacobs

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 inhib...Continue Reading

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Citations

Jun 27, 2013·Proceedings of the National Academy of Sciences of the United States of America·Sarah A StanleyDeborah T Hung
May 9, 2014·PLoS Pathogens·Catherine VilchèzeLaurent Kremer
Jul 12, 2013·Future Microbiology·Mary JacksonPatrick J Brennan
Sep 19, 2012·EMBO Molecular Medicine·Ruben C HartkoornStewart T Cole
Nov 11, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ondrej HolasMartin Dolezal
Aug 11, 2015·Chemistry and Physics of Lipids·Catherine VilchèzeWilliam R Jacobs
Jan 31, 2015·Journal of Chemical Information and Modeling·Alexander L PerrymanArthur J Olson
Feb 24, 2015·Immunological Reviews·Carl Nathan, Clifton E Barry
Mar 26, 2013·Chemistry & Biology·Sean EkinsJoel S Freundlich
Jul 20, 2016·EBioMedicine·María Martínez-HoyosAlfonso Mendoza-Losana
Dec 16, 2016·Parasitology·Katherine A Abrahams, Gurdyal S Besra
Jan 10, 2018·Antimicrobial Agents and Chemotherapy·Daigo InoyamaJoel S Freundlich
Oct 31, 2012·Expert Review of Anti-infective Therapy·Lorenza Favrot, Donald R Ronning
Feb 21, 2018·Future Medicinal Chemistry·Andrés GonzálezÁngel Lanas
Nov 13, 2019·Cell Chemical Biology·Xin WangJoel S Freundlich
Apr 2, 2021·Frontiers in Cellular and Infection Microbiology·Sangmi OhHelena I Boshoff
Mar 21, 2020·Cell Chemical Biology·Daigo InoyamaJoel S Freundlich
Feb 25, 2017·Microbiology Spectrum·Ben Gold, Carl Nathan
Oct 24, 2017·ACS Medicinal Chemistry Letters·Thomas P StrattonJoel S Freundlich

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