Zimhony O, Cox J S, Welch J T, Vilchèze C, Jacobs W R
Division of Infectious Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461, USA.
Nat Med. 2000 Sep;6(9):1043-7. doi: 10.1038/79558.
Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.
通过在包含异烟肼和利福平的药物方案中不可或缺地添加吡嗪酰胺（PZA），结核病治疗疗程缩短至六个月。PZA是吡嗪酸（POA）的前体药物（参考文献3），其作用靶点尚未确定。尽管PZA仅对结核分枝杆菌有活性，但PZA类似物5-氯吡嗪酰胺（5-Cl-PZA）具有更广泛的抗分枝杆菌活性。我们发现，来自鸟分枝杆菌、牛分枝杆菌卡介苗或结核分枝杆菌的类真核fas1基因（编码脂肪酸合成酶I，FASI），当在耻垢分枝杆菌的多拷贝载体上存在时，会赋予对5-Cl-PZA的抗性。5-Cl-PZA和PZA显著抑制结核分枝杆菌FASI的活性，以及从乙酰辅酶A合成C16至C24/C26脂肪酸（参考文献6）。重要的是，PZA抑制结核分枝杆菌中的FASI，且与PZA敏感性相关。这些结果表明，FASI是PZA在结核分枝杆菌中的主要作用靶点。将FASI进一步表征为PZA的药物靶点，可能有助于开发新药物以缩短抗结核治疗疗程，并可能为治疗牛分枝杆菌、鸟分枝杆菌和耐药结核分枝杆菌提供更多选择。
