PROTAC antibiotics: the time is now.
PROTAC antibiotics: the time is now.
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DOI：
10.1080/17460441.2023.2178413
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发表时间：
2023-04
影响因子：
6.3
通讯作者：
Dick, Thomas
中科院分区：
文献类型：
--
作者：
Sarathy, Jickky Palmae;Aldrich, Courtney C.;Go, Mei-Lin;Dick, Thomas
需要新型抗生素来控制抗生素耐药性，并改善对许多药物敏感感染的治疗，目前的治疗方法治愈率很低。虽然彻底改变了人类治疗方法，但通过双功能蛋白水解靶向嵌合体（PROTAC）的靶向蛋白降解（TPD）的概念尚未应用于抗生素的发现。阻止将该策略成功转化为抗生素开发的主要障碍是细菌缺乏人PROTAC利用的E3连接酶-蛋白酶体系统以促进靶降解。我们描述了第一个单功能靶向降解抗生素吡嗪酰胺的偶然发现，支持TPD作为抗生素发现的可行和新颖的方法。然后，我们讨论了第一个双功能抗菌靶标降解剂BacPROTAC的合理设计、机制和活性，从而为细菌中的TPD提供了一种可推广的方法。BacPROTAC证明，将靶标直接连接到细菌蛋白酶复合物可以促进靶标降解。BacPROTAC成功地绕过了“中间人”E3连接酶，为抗菌PROTAC的产生提供了进入策略。我们推测，抗菌PROTAC不仅将扩大靶向空间，而且还可以通过允许剂量减少、更强的杀菌活性和对耐药“坚持者”的活性来改善治疗。
Novel antibiotics are needed to keep antibiotic resistance at bay, and to improve treatment of the many drug-susceptible infections for which current therapies achieve poor cure rates. While revolutionizing human therapeutics, the concept of targeted protein degradation (TPD) by bifunctional proteolysis targeting chimeras (PROTACs) has not yet been applied to the discovery of antibiotics. A major obstacle precluding successful translation of this strategy to antibiotic development is that bacteria lack the E3 ligase-proteasome system exploited by human PROTACs to facilitate target degradation. We describe the serendipitous discovery of the first monofunctional target-degrading antibiotic pyrazinamide, supporting TPD as a viable and novel approach in antibiotic discovery. We then discuss the rational design, mechanism, and activity of the first bifunctional antibacterial target degrader BacPROTAC, enabling a generalizable approach to TPD in bacteria. BacPROTACs demonstrate that linking a target directly to a bacterial protease complex can promote target degradation. BacPROTACs successfully bypass the “middleman” E3 ligase, providing an entry strategy for the generation of antibacterial PROTACs. We speculate that antibacterial PROTACs will not only expand the target space but may also improve treatment by allowing dosage reduction, stronger bactericidal activity and activity against drug-tolerant “persisters”.
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影响因子：
5.2
作者：
Lin J;Nishino K;Roberts MC;Tolmasky M;Aminov RI;Zhang L
通讯作者：
Zhang L
影响因子：
5.3
作者：
Gopal P;Nartey W;Ragunathan P;Sarathy J;Kaya F;Yee M;Setzer C;Manimekalai MSS;Dartois V;Grüber G;Dick T
通讯作者：
Dick T
影响因子：
2.9
作者：
DeMonte, Daniel;Drake, Eric J.;Park, Sheldon
通讯作者：
Park, Sheldon
DOI：
10.1146/annurev-pharmtox-010715-103507
发表时间：
2017-01-06
影响因子：
12.5
作者：
Bondeson DP;Crews CM
通讯作者：
Crews CM
用于治疗脓肿分枝杆菌肺部疾病的抗生素的临床疗效和不良反应。
影响因子：
5.2
作者：
Chen, Jianhui;Zhao, Lan;Chu, Haiqing
通讯作者：
Chu, Haiqing