Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
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DOI：
10.1002/cmdc.200800047
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发表时间：
2008-08
期刊：
影响因子：
3.4
通讯作者：
Kozikowski, Alan P.
中科院分区：
文献类型：
--
作者：
Tipparaju, Suresh K.;Mulhearn, Debbie C.;Klein, Gary M.;Chen, Yufeng;Tapadar, Subhasish;Bishop, Molly H.;Yang, Shuo;Chen, Juan;Ghassemi, Mahmood;Santarsiero, Bernard D.;Cook, James L.;Johlfs, Mary;Mesecar, Andrew D.;Johnson, Michael E.;Kozikowski, Alan P.
The problem of increasing bacterial resistance to the current generation of antibiotics is well documented. This includes such pathogens as methicillin–resistant Staphylococcus aureus and the potential for developing drug–resistant pathogens for use as bioweapons, such as Bacillus anthracis. The biphenyl ether, antibacterial triclosan exhibits broad–spectrum activity and provides a potential scaffold for the development of new, broad–spectrum antibiotics targeting the fatty acid biosynthetic pathway, via inhibition of enoyl–acyl carrier protein reductase (ENR). We have utilized a structure–based approach to develop novel aryl ether analogs of triclosan that target ENR, the product of the FabI gene, from Bacillus anthracis (BaENR). Structure–based design methods were used for the expansion of the compound series including X-ray crystal structure determination, molecular docking, and QSAR methods. Structural modifications were made to both phenyl rings of the 2-phenoxyphenyl core. A number of compounds were derived that exhibited improved potency against BaENR and increased efficacy against both the Sterne strain of B. anthracis and the methicillin–resistant strain of S. aureus. X-ray crystal structures of BaENR in complex with triclosan and two other compounds help explain the improved efficacy of the new compounds and suggest future rounds of optimisation that might be used to improve their potency.
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影响因子：
3.6
作者：
Broussy, S;Bernardes-Génisson, V;Bernadou, J
通讯作者：
Bernadou, J
影响因子：
5.2
作者：
Escalada, MG;Harwood, JL;Ochs, D
通讯作者：
Ochs, D
DOI：
10.1038/nrd1694
发表时间：
2005-04
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Burnett JC;Henchal EA;Schmaljohn AL;Bavari S
通讯作者：
Bavari S
影响因子：
1.8
作者：
Evans, DA;Katz, JL;West, TR
通讯作者：
West, TR
影响因子：
120.7
作者：
Klevens, R. Monina;Morrison, Melissa A.;Fridkin, Scott K.
通讯作者：
Fridkin, Scott K.