Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues.
Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues.
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DOI：
10.1371/journal.pone.0053162
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kremer L
中科院分区：
文献类型：
--
作者：
Coxon GD;Craig D;Corrales RM;Vialla E;Gannoun-Zaki L;Kremer L
确定目前使用的药物的药理学靶点和开发具有更大效力的新类似物都是寻找有效对抗药物敏感性和耐药性结核分枝杆菌的药剂的重要方面。硫醋腙（TAC）是一种抗结核药物，以前与异烟肼一起使用，但由于毒副作用而从抗结核化疗药物库中删除。然而，最近的几项研究已经将TAC的作用机制与分枝菌酸代谢联系起来，并且TAC衍生的类似物已经显示出对分枝菌的增强效力。结核为了获得对TAC抗性的分子机制的新见解，我们分离并分析了10个M.对TAC高度耐药的结核病。发现一种菌株在甲基转移酶MmaA 4的Gly 101处发生突变，这与其缺乏含氧分枝菌酸一致。所有剩余的菌株在HadA（在Cys 61处）或HadC（在Val 85、Lys 157或Thr 123处）中具有错义突变，其是参与分枝菌酸延伸步骤的β-羟酰基-ACP脱氢酶复合物的组分。另外，合成了31个新的TAC类似物的文库，并针对M.结核这些化合物中的两种，15和16，表现出比亲本分子低10倍的最小抑制浓度，并以剂量依赖性方式抑制分枝菌酸生物合成。此外，HadAB、HadBC或HadABC在M.结核病导致对这些化合物的高水平抗性，表明它们的作用模式与TAC的作用模式相似。总之，这项研究发现了与TAC耐药性相关的新突变，也证明了TAC支架的简单结构优化是可能的，并可能导致新一代TAC衍生的候选药物作为分枝菌酸抑制剂用于结核病的潜在治疗。
Defining the pharmacological target(s) of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC) is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61) or HadC (at Val85, Lys157 or Thr123), which are components of the β-hydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors.
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影响因子：
4.8
作者：
Corrales, Rosa Milagros;Molle, Virginie;Kremer, Laurent
通讯作者：
Kremer, Laurent
影响因子：
3.6
作者：
Alahari, Anuradha;Alibaud, Laeticia;Kremer, Laurent
通讯作者：
Kremer, Laurent
影响因子：
4.8
作者：
Ojha, Anil K.;Trivelli, Xavier;Hatfull, Graham F.
通讯作者：
Hatfull, Graham F.
影响因子：
4.9
作者：
Dover, Lynn G.;Alahari, Anuradha;Kremer, Laurent
通讯作者：
Kremer, Laurent
影响因子：
56.3
作者：
Caminero, Jose A.;Sotgiu, Giovanni;Migliori, Giovanni Battista
通讯作者：
Migliori, Giovanni Battista