Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity. Issue 25 (23rd June 2016)

• Record Type: Journal Article
• Authors: Brackett, Christopher M.; Furlani, Robert E.; Anderson, Ryan G.; Krishnamurthy, Aparna; Melander, Roberta J.; Moskowitz, Samuel M.; Ernst, Robert K.; Melander, Christian
• Is Part Of: Tetrahedron. Volume 72:Issue 25(2016)
• Page Start: 3549
• Page End: 3553
• Publication Date: 2016-06-23
• Subjects: Antibiotic adjuvant -- 2-Aminoimidazole -- Colistin -- ESKAPE pathogens -- Acinetobacter baumannii -- Pseudomonas aeruginosa; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2015.09.019
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: 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. Graphical abstract: