title: Discovery of lead compounds targeting the bacterial sliding clamp using a fragment-based approach.
abstract: The bacterial sliding clamp (SC), also known as the DNA polymerase III β subunit, is an emerging antibacterial target that plays a central role in DNA replication, serving as a protein-protein interaction hub with a common binding pocket to recognize linear motifs in the partner proteins. Here, fragment-based screening using X-ray crystallography produced four hits bound in the linear-motif-binding pocket of the Escherichia coli SC. Compounds structurally related to the hits were identified that inhibited the E. coli SC and SC-mediated DNA replication in vitro. A tetrahydrocarbazole derivative emerged as a promising lead whose methyl and ethyl ester prodrug forms showed minimum inhibitory concentrations in the range of 21-43 μg/mL against representative Gram-negative and Gram-positive bacteria species. The work demonstrates the utility of a fragment-based approach for identifying bacterial sliding clamp inhibitors as lead compounds with broad-spectrum antibacterial activity.
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong , Wollongong, New South Wales 2522, Australia.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yin
authors.forename: Louise R
authors.initials: LR
authors.lastname: Whittell
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Slobodan
authors.initials: S
authors.lastname: Jergic
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Harry
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Dixon
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Beck
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Oakley
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D019295:Computational Biology; D018360:Crystallography, X-Ray; D004258:DNA Polymerase III / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004269:DNA, Bacterial / Q000096:biosynthesis / Q000187:drug effects; D015195:Drug Design; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016231:Fluorescence Polarization Immunoassay; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D010446:Peptide Fragments; C101139:beta subunit, DNA polymerase III; D004258:DNA Polymerase III