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Angucycline antibiotic waldiomycin recognizes common structural motif conserved in bacterial histidine kinases.

Eguchi Y, Okajima T, Tochio N, Inukai Y, Shimizu R, Ueda S, Shinya S, Kigawa T, Fukamizo T, Igarashi M, Utsumi R
J Antibiot (Tokyo) 70 251-258 (2017)
Cited: 17 times
EuropePMC logo PMID: 27999439

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.

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  2. Marginal specificity in protein interactions constrains evolution of a paralogous family. Ghose DA, Przydzial KE, Mahoney EM, Keating AE, Laub MT. Proc Natl Acad Sci U S A 120 e2221163120 (2023)


Reviews citing this publication (7)

  1. β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium. Fisher JF, Mobashery S. Chem Rev 121 3412-3463 (2021)
  2. Essential Two-Component Systems Regulating Cell Envelope Functions: Opportunities for Novel Antibiotic Therapies. Cardona ST, Choy M, Hogan AM. J Membr Biol 251 75-89 (2018)
  3. Host - Bacterial Pathogen Communication: The Wily Role of the Multidrug Efflux Pumps of the MFS Family. Pasqua M, Bonaccorsi di Patti MC, Fanelli G, Utsumi R, Eguchi Y, Trirocco R, Prosseda G, Grossi M, Colonna B. Front Mol Biosci 8 723274 (2021)
  4. Recent Advances in Histidine Kinase-Targeted Antimicrobial Agents. Chen H, Yu C, Wu H, Li G, Li C, Hong W, Yang X, Wang H, You X. Front Chem 10 866392 (2022)
  5. Bacterial signal transduction networks via connectors and development of the inhibitors as alternative antibiotics. Utsumi R. Biosci Biotechnol Biochem 81 1663-1669 (2017)
  6. Roles of Two-Component Signal Transduction Systems in Shigella Virulence. Pasqua M, Coluccia M, Eguchi Y, Okajima T, Grossi M, Prosseda G, Utsumi R, Colonna B. Biomolecules 12 1321 (2022)
  7. Microbial Genomics: Innovative Targets and Mechanisms. Alkatheri AH, Yap PS, Abushelaibi A, Lai KS, Cheng WH, Erin Lim SH. Antibiotics (Basel) 12 190 (2023)

Articles citing this publication (8)

  1. Essentiality and function of WalK/WalR two-component system: the past, present, and future of research. Takada H, Yoshikawa H. Biosci Biotechnol Biochem 82 741-751 (2018)
  2. The Signaling Molecule Indole Inhibits Induction of the AR2 Acid Resistance System in Escherichia coli. Boon N, Kaur M, Aziz A, Bradnick M, Shibayama K, Eguchi Y, Lund PA. Front Microbiol 11 474 (2020)
  3. The Two-Component Signaling System VraSRss Is Critical for Multidrug Resistance and Full Virulence in Streptococcus suis Serotype 2. Zhong X, Zhang Y, Zhu Y, Dong W, Ma J, Pan Z, Roy S, Lu C, Yao H. Infect Immun 86 e00096-18 (2018)
  4. Essentiality of WalRK for growth in Bacillus subtilis and its role during heat stress. Takada H, Shiwa Y, Takino Y, Osaka N, Ueda S, Watanabe S, Chibazakura T, Su'etsugu M, Utsumi R, Yoshikawa H. Microbiology (Reading) 164 670-684 (2018)
  5. Revisiting the pH-gated conformational switch on the activities of HisKA-family histidine kinases. Mideros-Mora C, Miguel-Romero L, Felipe-Ruiz A, Casino P, Marina A. Nat Commun 11 769 (2020)
  6. The Odyssey of the Ancestral Escherich Strain through Culture Collections: an Example of Allopatric Diversification. Desroches M, Royer G, Roche D, Mercier-Darty M, Vallenet D, Médigue C, Bastard K, Rodriguez C, Clermont O, Denamur E, Decousser JW. mSphere 3 e00553-17 (2018)
  7. A Large-Scale Mutational Analysis of Two-Component Signaling Systems of Lonsdalea quercina Revealed that KdpD-KdpE Regulates Bacterial Virulence Against Host Poplar Trees. Yang RL, Deng CY, Wei JW, He W, Li AN, Qian W. Mol Plant Microbe Interact 31 724-736 (2018)
  8. Mzabimycins A and B, novel intracellular angucycline antibiotics produced by Streptomyces sp. PAL114 in synthetic medium containing L-tryptophan. Tata S, Aouiche A, Bijani C, Bouras N, Pont F, Mathieu F, Sabaou N. Saudi Pharm J 27 907-913 (2019)


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