title: DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs.
abstract: Evidence suggests that some nonsteroidal anti-inflammatory drugs (NSAIDs) possess antibacterial properties with an unknown mechanism. We describe the in vitro antibacterial properties of the NSAIDs carprofen, bromfenac, and vedaprofen, and show that these NSAIDs inhibit the Escherichia coli DNA polymerase III β subunit, an essential interaction hub that acts as a mobile tether on DNA for many essential partner proteins in DNA replication and repair. Crystal structures show that the three NSAIDs bind to the sliding clamp at a common binding site required for partner binding. Inhibition of interaction of the clamp loader and/or the replicative polymerase α subunit with the sliding clamp is demonstrated using an in vitro DNA replication assay. NSAIDs thus present promising lead scaffolds for novel antibacterial agents targeting the sliding clamp.
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yin
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Whittell
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Jergic
authors.affiliation: iThree institute, University of Technology, Sydney, NSW 2007, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.affiliation: iThree institute, University of Technology, Sydney, NSW 2007, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harry
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Dixon
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Beck
authors.affiliation: School of Chemistry and Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia. Electronic address: aarono@uow.edu.au.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Oakley
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D004269:DNA, Bacterial / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004269:DNA, Bacterial; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; C101139:beta subunit, DNA polymerase III; D004258:DNA Polymerase III