Identification of KasA as the cellular target of an anti-tubercular scaffold.
Identification of KasA as the cellular target of an anti-tubercular scaffold.
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DOI：
10.1038/ncomms12581
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发表时间：
2016-09-01
影响因子：
16.6
通讯作者：
Bates, Robert H.
中科院分区：
文献类型：
--
作者：
Abrahams, Katherine A.;Chung, Chun-wa;Ghidelli-Disse, Sonja;Rullas, Joaquin;Jose Rebollo-Lopez, Maria;Gurcha, Sudagar S.;Cox, Jonathan A. G.;Mendoza, Alfonso;Jimenez-Navarro, Elena;Santos Martinez-Martinez, Maria;Neu, Margarete;Shillings, Anthony;Homes, Paul;Argyrou, Argyrides;Casanueva, Ruth;Loman, Nicholas J.;Moynihan, Patrick J.;Lelievre, Joel;Selenski, Carolyn;Axtman, Matthew;Kremer, Laurent;Bantscheff, Marcus;Angulo-Barturen, Inigo;Cacho Izquierdo, Monica;Cammack, Nicholas C.;Drewes, Gerard;Ballell, Lluis;Barros, David;Besra, Gurdyal S.;Bates, Robert H.
杀菌化合物的表型筛选开始对结核病产生有希望的治疗效果。在这方面，针对吲唑磺酰胺（GSK 3011724 A）产生的自发耐药突变体的全基因组测序确定了结核分枝杆菌β-酮脂酰合酶（kas）A基因中的几种特定单核苷酸多态性。在这里，这种基于基因组的靶点分配通过生化测定、化学蛋白质组学和通过X射线晶体学对KasA-GSK 3011724 A复合物的结构解析来证实。最后，M。结核病GSK 3011724 A抗性突变体增加了小鼠的体外最小抑制浓度和体内99%有效剂量，建立了体外和体内靶标接合。令人惊讶的是，与细菌中脂肪酸生物合成的其他Kas抑制剂相比，相关β-酮脂酰辅酶A酶（FabH和KasB）缺乏靶标接合表明了不同的抑制模式。这些结果清楚地鉴定了KasA为GSK 3011724 A的生物学靶标，并验证了这种酶用于进一步的抗结核药物发现工作。 杀菌化合物的筛选已经产生了有希望的抗结核药物。在这里，作者详细分析了吲唑磺酰胺（GSK 3011724 A）的靶点，发现与细菌中脂肪酸生物合成的其他Kas抑制剂相比，它具有不同的抑制模式。
Phenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis β-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related β-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis. Screens for bactericidal compounds have resulted in promising anti-tubercular hits. Here, the authors analyse in detail the target of an indazole sulfonamide (GSK3011724A), and find that it has a different mode of inhibition compared to other Kas inhibitors of fatty acid biosynthesis in bacteria.
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影响因子：
3.7
作者：
Coxon GD;Craig D;Corrales RM;Vialla E;Gannoun-Zaki L;Kremer L
通讯作者：
Kremer L
影响因子：
46.9
作者：
Bantscheff, Marcus;Hopf, Carsten;Drewes, Gerard
通讯作者：
Drewes, Gerard
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
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：
4.8
作者：
Kremer, L;Nampoothiri, KM;Besra, GS
通讯作者：
Besra, GS