Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents.
Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents.
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DOI：
10.1016/j.bmc.2022.117046
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发表时间：
2022-11-15
影响因子：
3.5
通讯作者：
Aldrich, Courtney C.
中科院分区：
文献类型：
--
作者：
V. Hegde, Pooja;Aragaw, Wassihun W.;Cole, Malcolm S.;Jachak, Gorakhnath;Ragunathan, Priya;Sharma, Sachin;Harikishore, Amaravadhi;Gruber, Gerhard;Dick, Thomas;Aldrich, Courtney C.
结核病 (TB) 仍然是传染病死亡率和发病率的主要原因。吡嗪酰胺 (PZA) 是一线结核病治疗方案的重要组成部分，因为它对非复制型结核分枝杆菌 (Mtb) 具有杀菌活性，但其作用机制仍然是个谜。 PZA 是一种前药，由 Mtb 内的 pncA 编码的吡嗪酰胺酶转化为活性部分吡嗪酸 (POA)，PZA 耐药性是由吡嗪酰胺酶的功能丧失突变引起的。我们最近发现 POA 会诱导 PanD 酶的靶向蛋白质降解，PanD 是 Mtb 中必需的辅酶 A 生物合成途径的重要组成部分。基于新发现的 POA 作用机制，以及与 POA 结合的 PanD 的晶体结构，我们设计了几种 POA 类似物，利用结构进行解释，以提高效力并克服 PZA 耐药性。我们制备并测试了环和羧酸生物等排体以及环上的3、5、6个取代基，以研究POA支架的结构活性关系。通过等温滴定量热法评估所有类似物的全细胞抗分枝杆菌活性，并评估一些代表性分子对 PanD 的结合亲和力。我们报告说，具有环和羧酸生物等排体的类似物并没有显着增强抗菌活性，而 POA 3 和 5 位的烷基氨基取代被发现比 POA 更有效 5 至 10 倍。这些类似物的进一步开发和机制分析可能会产生用于治疗结核病的下一代 POA 类似物。
Tuberculosis (TB) remains a leading cause of infectious disease mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10–fold more potent than POA. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB.
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影响因子：
4.9
作者：
Lu, Ping;Haagsma, Anna C.;Bald, Dirk
通讯作者：
Bald, Dirk
影响因子：
15
作者：
KUSHNER, S;DALALIAN, H;WILLIAMS, JH
通讯作者：
WILLIAMS, JH
影响因子：
2
作者：
Banerjee, Ranjan;Brown, Douglas R.;Weerapana, Eranthie
通讯作者：
Weerapana, Eranthie
影响因子：
4.9
作者：
Baughn, Anthony D.;Deng, Jiaoyu;Zimhony, Oren
通讯作者：
Zimhony, Oren
DOI：
10.1016/s0014-827x(03)00163-0
发表时间：
2003-11-01
期刊：
Farmaco (Lausanne)
影响因子：
--
作者：
Dolezal, M.;Jampilek, J.;Vichova, P.
通讯作者：
Vichova, P.