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

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 and Satoshi Ichikawa ()
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Kazuki Yamamoto: Hokkaido University, Kita-12, Nishi-6, Kita-ku
Toyotaka Sato: School/Faculty of Veterinary Medicine, Hokkaido University, Kita-18, Nishi-9, Kita-ku
Aili Hao: Duke University School of Medicine
Kenta Asao: Hokkaido University, Kita-12, Nishi-6, Kita-ku
Rintaro Kaguchi: Hokkaido University, Kita-12, Nishi-6, Kita-ku
Shintaro Kusaka: Hokkaido University, Kita-12, Nishi-6, Kita-ku
Radhakrishnam Raju Ruddarraju: Hokkaido University, Kita-12, Nishi-6, Kita-ku
Daichi Kazamori: Wakunaga Pharmaceutical Co., Ltd., 1624, Shimokotachi, Koda-cho, Akitakata-shi
Kiki Seo: Wakunaga Pharmaceutical Co., Ltd., 1624, Shimokotachi, Koda-cho, Akitakata-shi
Satoshi Takahashi: Sapporo Medical University Hospital, Minami-1, Nishi-16, Chuo-ku
Motohiro Horiuchi: School/Faculty of Veterinary Medicine, Hokkaido University, Kita-18, Nishi-9, Kita-ku
Shin-ichi Yokota: Sapporo Medical University School of Medicine, Minami-1, Nishi-17, Chuo-ku
Seok-Yong Lee: Duke University School of Medicine
Satoshi Ichikawa: Hokkaido University, Kita-12, Nishi-6, Kita-ku

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49484-7

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