Novel antibacterial compounds specifically targeting the essential WalR response regulator

The Journal of Antibiotics
Yasuhiro GotohRyutaro Utsumi

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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Citations

Dec 25, 2010·Applied Microbiology and Biotechnology·Norihiko MisawaKazutoshi Shindo
Feb 9, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Alexandre BerthierPhilippe Lefebvre
Apr 25, 2012·Antimicrobial Agents and Chemotherapy·Takafumi WatanabeRyutaro Utsumi
Jan 5, 2012·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Ryutaro Utsumi, Masayuki Igarashi
Jul 5, 2012·PLoS Pathogens·Wai-Leung NgBonnie L Bassler
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Feb 9, 2010·Current Opinion in Microbiology·Yasuhiro GotohRyutaro Utsumi
Nov 20, 2015·The Journal of General and Applied Microbiology·Md FakhruzzamanRyutaro Utsumi
Jan 3, 2013·Annals of the New York Academy of Sciences·Lynn L Silver
Nov 4, 2017·The Journal of Membrane Biology·Silvia T CardonaAndrew M Hogan
Mar 9, 2018·Bioscience, Biotechnology, and Biochemistry·Hiraku Takada, Hirofumi Yoshikawa
Dec 21, 2013·Pharmaceutical Patent Analyst·Thomas A KeatingJeroen C Verheijen
Feb 21, 2018·Future Medicinal Chemistry·Andrés GonzálezÁngel Lanas
Aug 21, 2019·Proceedings of the National Academy of Sciences of the United States of America·Melanie J BarnettSharon R Long
Oct 16, 2018·Frontiers in Microbiology·Hefa Mangzira KemungLearn-Han Lee
Oct 17, 2020·ACS Pharmacology & Translational Science·Wei ZhuWei Zheng

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