Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.
Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.
复制标题
通过靶向亚基界界面来抑制分枝杆菌色氨酸合酶。
DOI：
10.1038/s41598-017-09642-y
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发表时间：
2017-08-25
影响因子：
4.6
通讯作者：
Besra GS
中科院分区：
文献类型：
--
作者：
Abrahams KA;Cox JAG;Fütterer K;Rullas J;Ortega-Muro F;Loman NJ;Moynihan PJ;Pérez-Herrán E;Jiménez E;Esquivias J;Barros D;Ballell L;Alemparte C;Besra GS
通过对大量化合物库进行表型筛选，针对病原体结核分枝杆菌 (Mtb) 的药物发现工作取得了进展。这样的筛选表明环丁砜 1 和二氢吲哚-5-磺酰胺 2 和 3 是分枝杆菌生长的有效抑制剂。环丁砜系列的优化产生了化合物 4，该化合物已在 Mtb 感染的小鼠体内模型中证明具有活性。在这里，我们基于自发耐药突变体的全基因组测序确定了这些化合物的抑制靶点和模式，该突变体确定了位于色氨酸合酶必需的 α 和 β 亚基的突变。过度表达研究证实色氨酸合酶是生物靶标。生化技术探讨了抑制机制，揭示了突变酶复合物会产生适应性成本，但不会阻止抑制剂结合。将赋予突变抗性的突变映射到 Mtb 色氨酸合酶的低分辨率晶体结构上，表明它们位于 α 和 β 亚基之间的界面。抑制色氨酸合酶的抗结核药物的发现凸显了该酶的治疗潜力，并引起人们对其他氨基酸生物合成途径作为未来结核分枝杆菌药物靶点的前景的关注。
Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets.
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影响因子：
4.6
作者：
Cox JA;Mugumbate G;Del Peral LV;Jankute M;Abrahams KA;Jervis P;Jackenkroll S;Perez A;Alemparte C;Esquivias J;Lelièvre J;Ramon F;Barros D;Ballell L;Besra GS
通讯作者：
Besra GS
影响因子：
3.7
作者：
Jose Rebollo-Lopez, Maria;Lelievre, Joel;Barros-Aguire, David
通讯作者：
Barros-Aguire, David
影响因子：
4.9
作者：
Rullas, Joaquin;Ignacio Garcia, Juan;Angulo-Barturen, Inigo
通讯作者：
Angulo-Barturen, Inigo
影响因子：
3.7
作者：
Shen, Hongbo;Yang, Yanping;Wang, Honghai
通讯作者：
Wang, Honghai
影响因子：
3.7
作者：
Ryndak MB;Singh KK;Peng Z;Laal S
通讯作者：
Laal S