Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.
Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.
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DOI：
10.1016/j.chembiol.2012.09.018
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发表时间：
2012-12-21
影响因子：
--
通讯作者：
Sacchettini JC
中科院分区：
文献类型：
--
作者：
Krieger IV;Freundlich JS;Gawandi VB;Roberts JP;Gawandi VB;Sun Q;Owen JL;Fraile MT;Huss SI;Lavandera JL;Ioerger TR;Sacchettini JC
乙醛分流在脂肪酸代谢中起着重要作用，并已被证明是与慢性感染有关的几种病原体生存的关键。对于结核分枝杆菌(Mtb)，乙醛分流有缺陷的菌株以前被证明无法在小鼠模型中建立感染。我们报道了用基于结构的方法开发苹果酸合酶(GlcB)的新型苯基二酮酸(PDKA)抑制剂。PDKA抑制剂对生长在醋酸盐上的结核分枝杆菌有抑制作用，而GlcB的过表达可改善这种抑制作用。利用GlcB与PDKA抑制剂形成的络合物的晶体结构来指导药效的优化。一种精选的PDKA化合物在小鼠结核病模型中显示了疗效。这些PDKA衍生物的发现为GlcB作为结核病治疗的有吸引力的靶点提供了化学验证。
The glyoxylate shunt plays an important role in fatty-acid metabolism, and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of novel phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and over-expression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors were used to guide optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.
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影响因子：
8
作者：
Anstrom, DM;Kallio, K;Remington, SJ
通讯作者：
Remington, SJ
影响因子：
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作者：
Gengenbacher, Martin;Rao, Srinivasa P. S.;Dick, Thomas
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作者：
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KNOWLES, JR
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作者：
Beste DJ;Bonde B;Hawkins N;Ward JL;Beale MH;Noack S;Nöh K;Kruger NJ;Ratcliffe RG;McFadden J
通讯作者：
McFadden J
影响因子：
15
作者：
Berryman, Orion B.;Bryantsev, Vyacheslav S.;Hay, Benjamin P.
通讯作者：
Hay, Benjamin P.