한빛사논문
- 조회472
Takeshi Nakaya 1, Miyuki Yabe 1, Ellene H Mashalidis 2 3, Toyotaka Sato 4 5, Kazuki Yamamoto 1 6, Yuta Hikiji 1, Akira Katsuyama 1 6 7, Motoko Shinohara 8, Yusuke Minato 8, Satoshi Takahashi 9 10, Motohiro Horiuchi 4 5, Shin-Ichi Yokota 11, Seok-Yong Lee 12, Satoshi Ichikawa 13 14 15
1Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
2Department of Biochemistry, Duke University School of Medicine, Durham, NC, 27710, USA.
3Pfizer Global Research & Development, Eastern Point Road, Groton, CT, 06340, USA.
4Laboratory of Veterinary Hygiene, School/Faculty of Veterinary Medicine, Hokkaido University, Kita-18, Nishi-9, Kita-ku, Sapporo, 060-0818, Japan.
5Graduate School of Infectious Diseases, Hokkaido University, Sapporo, 060-0818, Japan.
6Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
7Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Sapporo, Japan.
8Department of Microbiology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
9Division of Laboratory Medicine, Sapporo Medical University Hospital, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
10Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
11Department of Microbiology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan.
12Department of Biochemistry, Duke University School of Medicine, Durham, NC, 27710, USA.
13Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
14Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
15Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812, Sapporo, Japan.
Corresponding authors : Correspondence to Seok-Yong Lee or Satoshi Ichikawa.
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.
논문정보
- Research article
- 2022년 12월 (BRIC 등록일 2023-01-12)
- 국외 연구진
- 생명과학 > 생화학
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