Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus.
Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus.
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DOI：
10.1021/jm5010682
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发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Flaherty DP
中科院分区：
文献类型：
--
作者：
Perlmutter JI;Forbes LT;Krysan DJ;Ebsworth-Mojica K;Colquhoun JM;Wang JL;Dunman PM;Flaherty DP
金黄色葡萄球菌在美国是一种迅速增长的健康威胁，对几种常用的处方药有抵抗力。高通量筛选确定抗组胺剂特非那定具有以前未报道的抗链球菌的抗菌活性。金黄色葡萄球菌和其他革兰氏阳性菌。为了改变这种药物的用途，结构-活性关系研究产生了84种基于特非那定的类似物，这些类似物经过几种修饰，与S.金黄色葡萄球菌和其他细菌病原体，包括结核分枝杆菌。作用机制研究表明，这些化合物发挥其抗菌作用，至少部分，通过抑制细菌II型拓扑异构酶。该支架具有hERG的缺陷，这一缺陷在这一轮优化中没有得到纠正;然而，考虑到该组活性的整体改善，基于特非那定的类似物提供了一种新型结构类别的抗微生物化合物，具有进一步表征的潜力，作为持续过程的一部分，以满足当前对新抗生素的需求。
Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure–activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.
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