Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity
Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity
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DOI：
10.1016/j.tet.2015.09.019
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发表时间：
2016-06-23
期刊：
影响因子：
2.1
通讯作者：
Melander, Christian
中科院分区：
文献类型：
--
作者：
Brackett, Christopher M.;Furlani, Robert E.;Melander, Christian
We recently reported a 2-aminoimidazole-based antibiotic adjuvant that reverses colistin resistance in two species of Gram-negative bacteria. Mechanistic studies in Acinetobacter baumannii demonstrated that this compound downregulated the PmrAB two-component system and abolished a lipid A modification that is required for colistin resistance. We now report the synthesis and evaluation of two separate libraries of substituted 2-aminoimidazole analogues based on this parent compound. From these libraries, a new small molecule was identified that lowers the minimum inhibitory concentration of colistin by up to 32-fold greater than the parent compound while also displaying less inherent bacterial toxicity, thereby minimizing the likelihood of resistance evolution. (C) 2015 Elsevier Ltd. All rights reserved.
