title: 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.
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kinki University, Nara, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Akihiro
authors.initials: A
authors.lastname: Doi
authors.forename: Eiji
authors.initials: E
authors.lastname: Furuta
authors.forename: Sarah
authors.initials: S
authors.lastname: Dubrac
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Ishizaki
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.forename: Masayuki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Misawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Toshihide
authors.initials: T
authors.lastname: Okajima
authors.forename: Tarek
authors.initials: T
authors.lastname: Msadek
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Utsumi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000302:isolation & purification; D002850:Chromatography, Gel; D015342:DNA Probes; D004269:DNA, Bacterial / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli / Q000235:genetics; D005456:Fluorescent Dyes; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008826:Microbial Sensitivity Tests; D010766:Phosphorylation; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D012329:RNA, Bacterial / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013050:Spectrometry, Fluorescence; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D014357:Trypsin / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015342:DNA Probes; D004269:DNA, Bacterial; D005456:Fluorescent Dyes; D012329:RNA, Bacterial; C119939:YycF protein, Bacteria; D014357:Trypsin