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Novel antibacterial compounds specifically targeting the essential WalR response regulator

Abstract : The WalK/WalR (YycG/YycF) two-component system, which is essential for cell viability, is highly conserved and specific to low-GC percentage of Gram-positive bacteria, making it an attractive target for novel antimicrobial compounds. Recent work has shown that WalK/WalR exerts an effect as a master regulatory system in controlling and coordinating cell wall metabolism with cell division in Bacillus subtilis and Staphylococcus aureus. In this paper, we develop a high-throughput screening system for WalR inhibitors and identify two novel inhibitors targeting the WalR response regulator (RR): walrycin A (4-methoxy-1-naphthol) and walrycin B (1,6-dimethyl-3-[4-(trifluoromethyl)phenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione). Addition of these compounds simultaneously affects the expression of WalR regulon genes, leading to phenotypes consistent with those of cells starved for the WalK/WalR system and having a bactericidal effect. B. subtilis cells form extremely long aseptate filaments and S. aureus cells form large aggregates under these conditions. These results show that walrycins A and B are the first antibacterial agents targeting WalR in B. subtilis and S. aureus.
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Submitted on : Tuesday, June 16, 2020 - 2:17:50 PM
Last modification on : Thursday, July 2, 2020 - 3:42:36 AM

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Yasuhiro Gotoh, Akihiro Doi, Eiji Furuta, Sarah Dubrac, Yoshimasa Ishizaki, et al.. Novel antibacterial compounds specifically targeting the essential WalR response regulator. Journal of Antibiotics, Nature Publishing Group: Open Access Hybrid Model Option B, 2010, 63 (3), pp.127-134. ⟨10.1038/ja.2010.4⟩. ⟨pasteur-02870035⟩

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