Marrakchi Hedia, Lanéelle Gilbert, Quémard Annaı K
Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, 205 route de Narbonne, 31077 Toulouse cedex, France1.
Microbiology (Reading). 2000 Feb;146 ( Pt 2):289-296. doi: 10.1099/00221287-146-2-289.
Most drug-resistant clinical isolates of the tubercle bacillus are resistant to isoniazid, a first-line antituberculous drug. This antibiotic was shown to act on Mycobacterium tuberculosis by inhibiting a 2-trans-enoyl-acyl carrier protein reductase, called InhA. However, the exact role played by InhA in mycobacteria remained unclear. A mycobacterial enzyme fraction containing InhA was isolated. It displays a long-chain fatty acid elongation activity with the characteristic properties described for the FAS-II (fatty acid synthetase II) system. Inhibition of this activity by InhA inhibitors, namely isoniazid, hexadecynoyl-CoA or octadecynoyl-CoA, showed that InhA belongs to the FAS-II system. Moreover, the InhA inhibitors also blocked the biosynthesis of mycolic acids, which are major lipids of the mycobacterial envelope. The data strongly suggest that isoniazid acts on the mycobacterial cell wall by preventing the FAS-II system from producing long-chain fatty acid precursors for mycolic acid biosynthesis.
大多数结核杆菌的耐药临床分离株对一线抗结核药物异烟肼耐药。这种抗生素被证明通过抑制一种名为InhA的2-反式烯酰-酰基载体蛋白还原酶作用于结核分枝杆菌。然而，InhA在分枝杆菌中的确切作用仍不清楚。分离出了一种含有InhA的分枝杆菌酶组分。它表现出长链脂肪酸延伸活性，具有脂肪酸合成酶II（FAS-II）系统所描述的特征特性。InhA抑制剂，即异烟肼、十六碳炔酰辅酶A或十八碳炔酰辅酶A对这种活性的抑制表明InhA属于FAS-II系统。此外，InhA抑制剂还阻断了分枝菌酸的生物合成，分枝菌酸是分枝杆菌包膜的主要脂质。这些数据有力地表明，异烟肼通过阻止FAS-II系统产生用于分枝菌酸生物合成的长链脂肪酸前体来作用于分枝杆菌细胞壁。
