In vitro inhibition of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA by isoniazid.

ABSTRACT: The first-line specific antituberculous drug isoniazid inhibits the fatty acid elongation system (FAS) FAS-II involved in the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The MabA protein that catalyzes the second step of the FAS-II elongation cycle is structurally and functionally related to the in vivo target of isoniazid, InhA, an NADH-dependent enoyl-acyl carrier protein reductase. The present work shows that the NADPH-dependent beta-ketoacyl reduction activity of MabA is efficiently inhibited by isoniazid in vitro by a mechanism similar to that by which isoniazid inhibits InhA activity. It involves the formation of a covalent adduct between Mn(III)-activated isoniazid and the MabA cofactor. Liquid chromatography-mass spectrometry analyses reveal

SUBMITTER: Ducasse-Cabanot S 

PROVIDER: S-EPMC310174 | biostudies-literature | 2004 Jan

REPOSITORIES: biostudies-literature