A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis
A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis
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DOI：
10.1126/science.1106753
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发表时间：
2005-01-14
期刊：
影响因子：
56.9
通讯作者：
Jarlier, V
中科院分区：
文献类型：
--
作者：
Andries, K;Verhasselt, P;Jarlier, V
在过去十年中，结核病的发病率在全世界范围内大幅度增加，但在40年中没有发现针对结核病的药物。我们确定了一个二芳基喹啉，R207910，有效地抑制药物敏感和耐药结核分枝杆菌在体外（最低抑制浓度0.06 μ g/ml）。在小鼠中，R207910超过异烟肼和利福平的杀菌活性至少1个对数单位。用R207910替代世界卫生组织的一线结核病治疗方案中的药物（利福平、异烟肼和吡嗪酰胺）可加速杀菌活性，导致某些组合治疗2个月后培养物完全转化。R207910单次给药可抑制分枝杆菌生长1周。在健康人类志愿者中，与小鼠有效性相关的血浆水平耐受良好。体外选择的突变体表明，该药物靶向三磷酸腺苷（ATP）合酶的质子泵。
The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.