Mutually Exclusive Genotypes for Pyrazinamide and 5-Chloropyrazinamide Resistance Reveal a Potential Resistance-Proofing Strategy
Mutually Exclusive Genotypes for Pyrazinamide and 5-Chloropyrazinamide Resistance Reveal a Potential Resistance-Proofing Strategy
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DOI：
10.1128/aac.00529-10
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发表时间：
2010-12-01
影响因子：
4.9
通讯作者：
Zimhony, Oren
中科院分区：
文献类型：
--
作者：
Baughn, Anthony D.;Deng, Jiaoyu;Zimhony, Oren
吡嗪酰胺 (PZA) 类似物 5-氯吡嗪酰胺 (5-Cl PZA) 对分枝杆菌具有活性，包括 PZA 耐药的结核分枝杆菌菌株。在耻垢分枝杆菌中，1 型脂肪酸合酶 (FAS I) 的过度表达赋予对 5-Cl PZA（一种有效的 FAS I 抑制剂）的抗性。由于结核分枝杆菌和牛分枝杆菌不能耐受 FAS I 过度表达，因此尚未描述结核杆菌的 5-Cl PZA 抗性突变。为了确定控制 5-Cl PZA 活性的其他因素，我们从转座子诱变的耻垢分枝杆菌分离株库中选择了 5-Cl PZA 抗性分离株。在这里，我们报告耻垢分枝杆菌吡嗪酰胺酶 PzaA 表达的增加赋予耻垢分枝杆菌、结核分枝杆菌和牛分枝杆菌对 5-Cl PZA 的抗性和对 PZA 的敏感性。相反，虽然结核分枝杆菌吡嗪酰胺酶 PncA 的异位过度表达会增加 PZA 敏感性，但该酰胺酶不会介导对 5-Cl PZA 的耐药性。我们得出的结论是，5-Cl PZA 的 PncA 独立周转代表了结核分枝杆菌对该化合物的潜在耐药机制，这可能会转化为 PZA 敏感性的增强。因此，当同时使用这些药物时，可以将反敏感性作为基于 PZA 的化合物的抗耐药性策略。
The pyrazinamide (PZA) analog 5-chloropyrazinamide (5-Cl PZA) is active against mycobacterial species, including PZA-resistant strains of Mycobacterium tuberculosis. In M. smegmatis, overexpression of the type 1 fatty acid synthase (FAS I) confers resistance to 5-Cl PZA, a potent FAS I inhibitor. Since M. tuberculosis and M. bovis cannot tolerate FAS I overexpression, 5-Cl PZA resistance mutations have yet to be described for tubercle bacilli. In an attempt to identify other factors that govern the activity of 5-Cl PZA, we selected for 5-Cl PZA-resistant isolates from a library of transposon-mutagenized M. smegmatis isolates. Here, we report that increased expression of the M. smegmatis pyrazinamidase PzaA confers resistance to 5-Cl PZA and susceptibility to PZA in M. smegmatis, M. tuberculosis, and M. bovis. In contrast, while ectopic overexpression of the M. tuberculosis pyrazinamidase PncA increases PZA susceptibility, this amidase does not mediate resistance to 5-Cl PZA. We conclude that PncA-independent turnover of 5-Cl PZA represents a potential mechanism of resistance to this compound for M. tuberculosis, which will likely translate into enhanced PZA susceptibility. Thus, countersusceptibility can be manipulated as a resistance-proofing strategy for PZA-based compounds when these agents are used simultaneously.