Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY

Takeshi Nakaya, Miyuki Yabe, Ellene H. Mashalidis, Toyotaka Sato, Kazuki Yamamoto, Yuta Hikiji, Akira Katsuyama, Motoko Shinohara, Yusuke Minato, Satoshi Takahashi, Motohiro Horiuchi, Shin-ichi Yokota, Seok-Yong Lee () and Satoshi Ichikawa ()
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Takeshi Nakaya: Hokkaido University
Miyuki Yabe: Hokkaido University
Ellene H. Mashalidis: Duke University School of Medicine
Toyotaka Sato: Hokkaido University
Kazuki Yamamoto: Hokkaido University
Yuta Hikiji: Hokkaido University
Akira Katsuyama: Hokkaido University
Motoko Shinohara: Fujita Health University School of Medicine
Yusuke Minato: Fujita Health University School of Medicine
Satoshi Takahashi: Sapporo Medical University Hospital
Motohiro Horiuchi: Hokkaido University
Shin-ichi Yokota: Sapporo Medical University School of Medicine
Seok-Yong Lee: Duke University School of Medicine
Satoshi Ichikawa: Hokkaido University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35227-z

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