DNA Replication Is the Target for the Antibacterial Effects of Nonsteroidal Anti-Inflammatory Drugs

被引：101

作者：

Yin, Zhou ^{[1
,2
]}

Wang, Yao ^{[1
,2
]}

Whittell, Louise R. ^{[1
,2
]}

Jergic, Slobodan ^{[1
,2
]}

Liu, Michael ^{[3
]}

Harry, Elizabeth ^{[3
]}

Dixon, Nicholas E. ^{[1
,2
]}

Kelso, Michael J. ^{[1
,2
]}

Beck, Jennifer L. ^{[1
,2
]}

Oakley, Aaron J. ^{[1
,2
]}

机构：

[1] Univ Wollongong, Sch Chem, Wollongong, NSW 2522, Australia

[2] Univ Wollongong, Ctr Med & Mol Biosci, Wollongong, NSW 2522, Australia

[3] Univ Technol Sydney, IThree Inst, Sydney, NSW 2007, Australia

来源：

CHEMISTRY & BIOLOGY | 2014年 / 21卷 / 04期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

POLYMERASE-III HOLOENZYME; BETA-SLIDING-CLAMP; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; DELTA-SUBUNIT; PROTEIN; MACHINE; COMPLEX; BINDING; LOADER;

D O I：

10.1016/j.chembiol.2014.02.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta 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 alpha 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.

引用

页码：481 / 487

页数：7

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