天然产物
药物发现
计算生物学
天然产物研究
抗菌剂
组合化学
体内
小分子
结构-活动关系
化学
生化工程
体外
生物
生物化学
生物活性
微生物学
生物技术
生药学
工程类
作者
Kazuki Yamamoto,Toyotaka Sato,Aili Hao,Kenta Asao,Rintaro Kaguchi,Shintaro Kusaka,Radhakrishnam Raju Ruddarraju,Daichi Kazamori,Kiki Seo,Satoshi Takahashi,Motohiro Horiuchi,Shin‐ichi Yokota,Seok‐Yong Lee,Satoshi Ichikawa
标识
DOI:10.1038/s41467-024-49484-7
摘要
Abstract MraY (phospho- N -acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.
科研通智能强力驱动
Strongly Powered by AbleSci AI