title: Angucycline antibiotic waldiomycin recognizes common structural motif conserved in bacterial histidine kinases.
abstract: Two-component signal transduction systems (TCSs), composed of a histidine kinase sensor (HK) and its cognate response regulator, sense and respond to environmental changes and are related to the virulence of pathogens. TCSs are potential targets for alternative antibiotics and anti-virulence agents. Here we found that waldiomycin, an angucycline antibiotic that inhibits a growth essential HK, WalK, in Gram-positive bacteria, also inhibits several class I HKs from the Gram-negative Escherichia coli. NMR analyses and site-directed mutagenesis studies using the osmo-sensing EnvZ, a prototypical HK of E. coli, showed that waldiomycin directly binds to both H-box and X-region, which are the two conserved regions in the dimerization-inducing and histidine-containing phosphotransfer (DHp) domain of HKs. Waldiomycin inhibits phosphorylation of the conserved histidine in the H-box. Analysis of waldiomycin derivatives suggests that the angucyclic ring, situated near the H-box in the waldiomycin-EnvZ DHp domain complex model, is responsible for the inhibitory activity. We demonstrate that waldiomycin is an HK inhibitor binding to the H-box region and has the potential of inhibiting a broad spectrum of HKs.
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.|Department of Science and Technology on Food Safety, Kindai University, Kinokawa, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Eguchi
authors.affiliation: Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Japan.|Department of Chemistry, Osaka Medical College, Takatsuki, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Okajima
authors.affiliation: Research Center for the Mathematics on Chromatin Live Dynamics, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Japan.|RIKEN Systems and Structural Biology Center, Yokohama, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Tochio
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Inukai
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.
authors.forename: Riko
authors.initials: R
authors.lastname: Shimizu
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Shinya
authors.affiliation: RIKEN Systems and Structural Biology Center, Yokohama, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kigawa
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.
authors.forename: Tamo
authors.initials: T
authors.lastname: Fukamizo
authors.affiliation: Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Department of Bioscience, Graduate School of Agriculture, Kindai University, Nara, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Utsumi
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D017124:Conserved Sequence; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D000071677:Histidine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D008961:Models, Structural; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011809:Quinones / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; D009097:Multienzyme Complexes; D011809:Quinones; C584027:waldiomycin; D000071677:Histidine Kinase; C057843:envZ protein, E coli