RRC ID 53615
Author Arita-Morioka K, Yamanaka K, Mizunoe Y, Ogura T, Sugimoto S.
Title Novel strategy for biofilm inhibition by using small molecules targeting molecular chaperone DnaK.
Journal Antimicrob Agents Chemother
Abstract Biofilms are complex communities of microorganisms that attach to surfaces and are embedded in a self-produced extracellular matrix. Since these cells acquire increased tolerance against antimicrobial agents and host immune systems, biofilm-associated infectious diseases tend to become chronic. We show here that the molecular chaperone DnaK is important for biofilm formation and that chemical inhibition of DnaK cellular functions is effective in preventing biofilm development. Genetic, microbial, and microscopic analyses revealed that deletion of the dnaK gene markedly reduced the production of the extracellular functional amyloid curli, which contributes to the robustness of Escherichia coli biofilms. We tested the ability of DnaK inhibitors myricetin (Myr), telmisartan, pancuronium bromide, and zafirlukast to prevent biofilm formation of E. coli. Only Myr, a flavonol widely distributed in plants, inhibited biofilm formation in a concentration-dependent manner (50% inhibitory concentration [IC50] = 46.2 μM); however, it did not affect growth. Transmission electron microscopy demonstrated that Myr inhibited the production of curli. Phenotypic analyses of thermosensitivity, cell division, intracellular level of RNA polymerase sigma factor RpoH, and vulnerability to vancomycin revealed that Myr altered the phenotype of E. coli wild-type cells to make them resemble those of the isogenic dnaK deletion mutant, indicating that Myr inhibits cellular functions of DnaK. These findings provide insights into the significance of DnaK in curli-dependent biofilm formation and indicate that DnaK is an ideal target for antibiofilm drugs.
Volume 59(1)
Pages 633-41
Published 2015-1-1
DOI 10.1128/AAC.04465-14
PII AAC.04465-14
PMID 25403660
PMC PMC4291377
MeSH Benzimidazoles / pharmacology Benzoates / pharmacology Biofilms / drug effects* Dose-Response Relationship, Drug Escherichia coli / drug effects* Escherichia coli / physiology Escherichia coli Proteins / antagonists & inhibitors* Escherichia coli Proteins / genetics Escherichia coli Proteins / metabolism Flavonoids / pharmacology HSP70 Heat-Shock Proteins / antagonists & inhibitors* HSP70 Heat-Shock Proteins / genetics HSP70 Heat-Shock Proteins / metabolism Indoles Inhibitory Concentration 50 Methicillin-Resistant Staphylococcus aureus / drug effects Methicillin-Resistant Staphylococcus aureus / physiology Molecular Chaperones / metabolism Molecular Targeted Therapy Pancuronium / pharmacology Phenylcarbamates Staphylococcus aureus / drug effects Staphylococcus aureus / physiology Sulfonamides Telmisartan Tosyl Compounds / pharmacology Vancomycin / pharmacology
IF 4.904
Times Cited 37
Prokaryotes E. coli