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Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY

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Title: Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY
Authors: Nakaya, Takeshi Browse this author
Yabe, Miyuki Browse this author
Mashalidis, Ellene H. Browse this author
Sato, Toyotaka Browse this author →KAKEN DB
Yamamoto, Kazuki Browse this author →KAKEN DB
Hikiji, Yuta Browse this author
Katsuyama, Akira Browse this author →KAKEN DB
Shinohara, Motoko Browse this author
Minato, Yusuke Browse this author →KAKEN DB
Takahashi, Satoshi Browse this author →KAKEN DB
Horiuchi, Motohiro Browse this author →KAKEN DB
Yokota, Shin-ichi Browse this author →KAKEN DB
Lee, Seok-Yong Browse this author
Ichikawa, Satoshi Browse this author →KAKEN DB
Issue Date: 20-Dec-2022
Publisher: Nature Portfolio
Journal Title: Nature communications
Volume: 13
Issue: 1
Start Page: 7575
Publisher DOI: 10.1038/s41467-022-35227-z
Abstract: The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria. MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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