Medicine and Health

Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target

K. Yamamoto, T. Sato, et al.

MraY inhibitory natural products could revolutionize the fight against antimicrobial-resistant bacteria, showcasing potent antibacterial activities *in vitro* and *in vivo*. This ambitious research, carried out by a team of experts including Kazuki Yamamoto and Aili Hao, explores innovative strategies for evaluating inhibitors while revealing unique binding modes.

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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. This paper develops a strategy for comprehensive *in situ* evaluation of a build-up library to streamline analogue preparation and directly assess biological activities. Applying this to MraY inhibitors, 686 compounds were identified, with promising analogues showing potent, broad-spectrum antibacterial activity *in vitro* and *in vivo*. MraY-analogue complex structures reveal unique binding modes. The strategy's generality is demonstrated using tubulin-binding natural products.

Publisher

Nature Communications

Published On

Jun 14, 2024

Authors

Kazuki Yamamoto, Toyotaka Sato, Aili Hao, Kenta Asao, Rintaro Kaguchi, Shintaro Kusaka, Radhakrishnam Raju Ruddarraju, Daichi Kazamori, Kiki Seo, Satoshi Takahashi, Motohiro Horiuchi, Shin-ichi Yokota, Seok-Yong Lee, Satoshi Ichikawa

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