title: Small molecule DnaK modulators targeting the beta-domain.
abstract: The molecular chaperone DnaK is essential for the survival of bacterial pathogens in the hostile environment of the host. Hence, it is in principle a promising target for drug design but for which no current inhibitors are available apart from certain antimicrobial peptides. To this end, we have screened libraries of small molecules for their ability to interact with the substrate-binding domain of DnaK. The most promising hit from the screen was synthesized and along with its analogs subjected to further assays to determine their binding affinity and ability to interfere with bacterial growth. This work resulted in the identification of a number of compounds that bind with submicromolar affinity and capable of inhibiting Yersinia pseudotuberculosis growth more effectively than the previously characterized peptides.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Cellitti
authors.forename: Ziming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: Patty
authors.initials: P
authors.lastname: Hasegawa
authors.forename: Donald G
authors.initials: DG
authors.lastname: Guiney
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; C063842:dnaK protein, E coli
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