DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs

Yin, Z; Wang, Y; Whittell, LR; Jergic, S; Liu, M; Harry, E; Dixon, NE; Kelso, MJ; Beck, JL; Oakley, AJ

DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs

Yin, Z Wang, Y Whittell, LR Jergic, S Liu, M

Harry, E

Dixon, NE Kelso, MJ Beck, JL Oakley, AJ

Permalink

Publication Type:: Journal Article
Citation:: Chemistry and Biology, 2014, 21 (4), pp. 481 - 487
Issue Date:: 2014-04-24

Closed Access

	Filename	Description	Size
	1-s2.0-S1074552114000672-main.pdf	Accepted Manuscript Version	1.54 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Yin, Z	en_US
dc.contributor.author	Wang, Y	en_US
dc.contributor.author	Whittell, LR	en_US
dc.contributor.author	Jergic, S	en_US
dc.contributor.author	Liu, M https://orcid.org/0000-0001-8312-0734	en_US
dc.contributor.author	Harry, E https://orcid.org/0000-0003-0858-9473	en_US
dc.contributor.author	Dixon, NE	en_US
dc.contributor.author	Kelso, MJ	en_US
dc.contributor.author	Beck, JL	en_US
dc.contributor.author	Oakley, AJ	en_US
dc.date.available	2014-02-13	en_US
dc.date.issued	2014-04-24	en_US
dc.identifier.citation	Chemistry and Biology, 2014, 21 (4), pp. 481 - 487	en_US
dc.identifier.issn	1074-5521	en_US
dc.identifier.uri	http://hdl.handle.net/10453/65275
dc.description.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. © 2014 Elsevier Ltd. All rights reserved.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1021479
dc.relation.ispartof	Chemistry and Biology	en_US
dc.relation.isbasedon	10.1016/j.chembiol.2014.02.009	en_US
dc.subject.classification	Organic Chemistry	en_US
dc.subject.mesh	Escherichia coli	en_US
dc.subject.mesh	DNA Polymerase III	en_US
dc.subject.mesh	Protein Subunits	en_US
dc.subject.mesh	DNA, Bacterial	en_US
dc.subject.mesh	Anti-Inflammatory Agents, Non-Steroidal	en_US
dc.subject.mesh	Protein Kinase Inhibitors	en_US
dc.subject.mesh	Anti-Bacterial Agents	en_US
dc.subject.mesh	DNA Replication	en_US
dc.subject.mesh	Structure-Activity Relationship	en_US
dc.subject.mesh	Dose-Response Relationship, Drug	en_US
dc.subject.mesh	Models, Molecular	en_US
dc.title	DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	21	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
dcterms.accessRights	Closed Access. Free to read version at https://doi.org/10.1016/j.chembiol.2014.02.009
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	21	en_US

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. © 2014 Elsevier Ltd. All rights reserved.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/65275