| 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 |
| URI: | http://hdl.handle.net/2115/89035 |
| Appears in Collections: | 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)
薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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