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  3. Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases

Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases

  • J Antibiot (Tokyo). 2024 Jun 25. doi: 10.1038/s41429-024-00726-2.
Teruhiko Ishikawa # 1,  Yoko Eguchi # 2,  Masayuki Igarashi # 3,  Toshihide Okajima # 4,  Kohei Mita 5,  Yuri Yamasaki 5,  Kaho Sumikura 5,  Taisei Okumura 5,  Yuna Tabuchi 5,  Chigusa Hayashi 3,  Martina Pasqua 6,  Marco Coluccia 6,  Gianni Prosseda 6,  Bianca Colonna 6,  Chie Kohayakawa 7,  Akiyoshi Tani 8,  Jun-Ichi Haruta 7,  Ryutaro Utsumi # 9
Affiliations

Affiliations

  • 1 Graduate School of Education, Okayama University, Okayama, Japan. teruhiko@cc.okayama-u.ac.jp.
  • 2 Department of Science and Technology on Food Safety, Faculty of Biology-Oriented Science and Technology, Kindai University, Wakayama, Japan.
  • 3 Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.
  • 4 SANKEN (The Institute of Scientific and Industrial Research), Osaka University, Osaka, Japan.
  • 5 Graduate School of Education, Okayama University, Okayama, Japan.
  • 6 Istituto Pasteur Italy, Department of Biology and Biotechnology, "C. Darwin", Sapienza University of Rome, Rome, Italy.
  • 7 Department of Lead Exploration Units, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
  • 8 Compound Library Screening Center, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
  • 9 SANKEN (The Institute of Scientific and Industrial Research), Osaka University, Osaka, Japan. utsumi@sanken.osaka-u.ac.jp.
  • # Contributed equally.
PMID: 38918599 DOI: 10.1038/s41429-024-00726-2
Abstract

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized. These compounds were tested for their inhibitory activity (IC50) against WalK, an essential HK for Bacillus subtilis growth, and their minimum inhibitory concentrations (MIC) against B. subtilis. As a result, 11 novel HK inhibitors were obtained as naphthoquinone derivatives (IC50: 12.6-305 µM, MIC: 0.5-128 µg ml-1). The effect of representative compounds on the expression of WalK/WalR regulated genes in B. subtilis was investigated. Four naphthoquinone derivatives induced the expression of iseA (formerly yoeB), whose expression is negatively regulated by the WalK/WalR system. This suggests that these compounds inhibit WalK in B. subtilis cells, resulting in Antibacterial activity. Affinity selection/mass spectrometry analysis was performed to identify whether these naphthoquinone derivatives interact with WalK in a manner similar to waldiomycin. Three compounds were found to competitively inhibit the binding of waldiomycin to WalK, suggesting that they bind to the H-box region conserved in HKs and inhibit HK activity.

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