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

Zhou Yin; Yao Wang; Louise R. Whittell; Slobodan Jergic; Michael Liu; Elizabeth Harry; Nicholas E. Dixon; Michael J. Kelso; Jennifer L. Beck; Aaron J. Oakley

doi:10.1016/j.chembiol.2014.02.009

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

Zhou Yin, Yao Wang, Louise R. Whittell, Slobodan Jergic, Michael Liu, Elizabeth Harry, Nicholas E. Dixon, Michael J. Kelso, Jennifer L. Beck, Aaron J. Oakley

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

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.

Original language	English (US)
Pages (from-to)	481-487
Number of pages	7
Journal	Chemistry and Biology
Volume	21
Issue number	4
DOIs	https://doi.org/10.1016/j.chembiol.2014.02.009
State	Published - Apr 24 2014
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2014.02.009

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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.",

author = "Zhou Yin and Yao Wang and Whittell, {Louise R.} and Slobodan Jergic and Michael Liu and Elizabeth Harry and Dixon, {Nicholas E.} and Kelso, {Michael J.} and Beck, {Jennifer L.} and Oakley, {Aaron J.}",

note = "Funding Information: We thank the staff at Beamline MX1, Australian Synchrotron. This research was supported by an Australian Research Council (ARC) Discovery Project (DP110100660) and National Health and Medical Research Council (Australia) Project Grant (1021479). A.J.O. acknowledges support from the ARC for his Future Fellowship (FT0990287). ",

year = "2014",

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doi = "10.1016/j.chembiol.2014.02.009",

language = "English (US)",

volume = "21",

pages = "481--487",

journal = "Chemistry and Biology",

issn = "1074-5521",

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T1 - DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs

AU - Yin, Zhou

AU - Wang, Yao

AU - Whittell, Louise R.

AU - Jergic, Slobodan

AU - Liu, Michael

AU - Harry, Elizabeth

AU - Dixon, Nicholas E.

AU - Kelso, Michael J.

AU - Beck, Jennifer L.

AU - Oakley, Aaron J.

N1 - Funding Information: We thank the staff at Beamline MX1, Australian Synchrotron. This research was supported by an Australian Research Council (ARC) Discovery Project (DP110100660) and National Health and Medical Research Council (Australia) Project Grant (1021479). A.J.O. acknowledges support from the ARC for his Future Fellowship (FT0990287).

PY - 2014/4/24

Y1 - 2014/4/24

N2 - 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.

AB - 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.

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JO - Chemistry and Biology

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

Abstract

ASJC Scopus subject areas

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