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- Title
Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.
- Authors
Yamamoto, Kazuki; Sato, Toyotaka; Hao, Aili; Asao, Kenta; Kaguchi, Rintaro; Kusaka, Shintaro; Ruddarraju, Radhakrishnam Raju; Kazamori, Daichi; Seo, Kiki; Takahashi, Satoshi; Horiuchi, Motohiro; Yokota, Shin-ichi; Lee, Seok-Yong; Ichikawa, Satoshi
- Abstract
MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities. MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive candidates for the development of agents to combat antimicrobial-resistant bacteria, but their properties need to be improved by structural optimization which is challenging. Here, the authors develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables streamlining of the preparation of the analogue library and direct assessment of its biological activities.
- Subjects
NATURAL products; NEW product development; STRUCTURAL optimization; ANTIBACTERIAL agents
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49484-7