Journal Article

Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases

Kohayakawa, Chie, Eguchi, Yoko, Igarashi, Masayuki, Yamasaki, Yuri, Utsumi, Ryutaro, Okajima, Toshihide, Hayashi, Chigusa, Tabuchi, Yuna, Coluccia, Marco, Okumura, Taisei, Colonna, Bianca, Haruta, Jun-ichi, Pasqua, Martina, Ishikawa, Teruhiko, Mita, Kohei, Tani, Akiyoshi, Sumikura, Kaho, Prosseda, Gianni

2024

Overview

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 (IC 50 ) 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 (IC 50 : 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.

• Publisher: Springer Science and Business Media LLC,Springer Japan,Nature Publishing Group
• Subject: 13/95 / 38/39 / 38/77 / 631/154/309/2144 / 631/92/613 / 82/16 / 82/29 / 96/98 / Amino groups / Anti-Bacterial Agents - chemical synthesis / Anti-Bacterial Agents - chemistry / Anti-Bacterial Agents - pharmacology / Antibacterial activity / Bacillus subtilis - drug effects / Bacterial Proteins - antagonists & inhibitors / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Bacteriology / Binding / Biomedical and Life Sciences / Bioorganic Chemistry / Diketones / Dimerization / drug discovery; drug development; small molecules; two component system; histidine kinase / Drug resistance / Gene expression / Gene Expression Regulation, Bacterial / Histidine / Histidine Kinase - antagonists & inhibitors / Histidine Kinase - metabolism / Inhibitors / Kinases / Life Sciences / Mass spectrometry / Mass spectroscopy / Medicinal Chemistry / Microbial Sensitivity Tests / Microbiology / Minimum inhibitory concentration / Naphthoquinones - chemical synthesis / Naphthoquinones - chemistry / Naphthoquinones - pharmacology / Organic Chemistry / Oxidation / Pathogens / Pharmaceutical sciences / Plasmids / Protein Kinase Inhibitors - chemical synthesis / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Quinones / Signal transduction / Structure-Activity Relationship