Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity

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• 作者：Christopher M. Brackett^a ; Robert E. Furlani^a ; Ryan G. Anderson^a ; Aparna Krishnamurthy^a ; Roberta J. Melander^a ; Samuel M. Moskowitz^b ; Robert K. Ernst^c ; Christian Melander^a ; ^{ccmeland@ncsu.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Antibiotic adjuvant ; 2-Aminoimidazole ; Colistin ; ESKAPE pathogens ; Acinetobacter baumannii ; Pseudomonas aeruginosa
• 刊名：Tetrahedron
• 出版年：2016
• 出版时间：23 June 2016
• 年：2016
• 卷：72
• 期：25
• 页码：3549-3553
• 全文大小：767 K

文摘

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.