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- Title
Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY.
- Authors
Nakaya, Takeshi; Yabe, Miyuki; Mashalidis, Ellene H.; Sato, Toyotaka; Yamamoto, Kazuki; Hikiji, Yuta; Katsuyama, Akira; Shinohara, Motoko; Minato, Yusuke; Takahashi, Satoshi; Horiuchi, Motohiro; Yokota, Shin-ichi; Lee, Seok-Yong; Ichikawa, Satoshi
- 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.
- Subjects
NUCLEOSIDE synthesis; MACROCYCLIC compounds; ANTIBACTERIAL agents; BACTERIAL enzymes; BACTERIAL cell walls; GRAM-positive bacteria; DRUG resistance in microorganisms
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-35227-z