InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II

Most drug-resistant clinical isolates of the tubercle bacillus are resistan t to isoniazid, a first-line antituberculous drug. This antibiotic was show n to act on Mycobacterium tuberculosis by inhibiting a 2-trans-enoyl-acyl c arrier protein reductase, called InhA, However, the exact role played by In hA in mycobacteria remained unclear. A mycobacterial enzyme fraction contai ning InhA was isolated. It displays a long-chain fatty acid elongation acti vity with the characteristic properties described for the FAS-II (fatty aci d synthetase II) system. Inhibition of this activity by InhA inhibitors, na mely isoniazid, hexadecynoyl-CoA or octadecynoyl-CoA. showed that InhA belo ngs to the FAS-II system. Moreover, the InhA inhibitors also blocked the bi osynthesis of mycolic acids, which are major lipids of the mycobacterial en velope. The data strongly suggest that isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty a cid precursors for mycolic acid biosynthesis.