title: Screening and evaluation of small organic molecules as ClpB inhibitors and potential antimicrobials.
abstract: Inhibition of ClpB, the bacterial representative of the heat-shock protein 100 family that is associated with virulence of several pathogens, could be an effective strategy to develop new antimicrobial agents. Using a high-throughput screening method, we have identified several compounds that bind to different conformations of ClpB and analyzed their effect on the ATPase and chaperone activities of the protein. Two of them inhibit these functional properties as well as the growth of Gram negative bacteria (E. coli), displaying antimicrobial activity under thermal or oxidative stress conditions. This activity is abolished upon deletion of ClpB, indicating that the action of these compounds is related to the stress cellular response in which ClpB is involved. Moreover, their moderate toxicity in human cell lines suggests that they might provide promising leads against bacterial growth.
authors: Biophysics Unit (CSIC-UPV/EHU) and Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU) , 48080 Bilbao, Spain.
authors: Ianire
authors: I
authors: Martin
authors: Jarl
authors: J
authors: Underhaug
authors: Garbiñe
authors: G
authors: Celaya
authors: Fernando
authors: F
authors: Moro
authors: Knut
authors: K
authors: Teigen
authors: Aurora
authors: A
authors: Martinez
authors: Arturo
authors: A
authors: Muga
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D017353:Gene Deletion; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D009930:Organic Chemicals / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D013696:Temperature
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D009930:Organic Chemicals; D000251:Adenosine Triphosphatases