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

TETRAHEDRON

卷:72

Article

Brackett, Christopher M.¹  Furlani, Robert E.¹  Anderson, Ryan G.¹  Krishnamurthy, Aparna¹  Melander, Roberta J.¹  Moskowitz, Samuel M.^2,3  Ernst, Robert K.⁴  Melander, Christian¹ 

[1] N Carolina State Univ, Dept Chem, Box 8204, Raleigh, NC 27695 USA

[2] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA 02114 USA

[4] Univ Maryland, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA

关键词: Antibiotic adjuvant;    2-Aminoimidazole;    Colistin;    ESKAPE pathogens;    Acinetobacter baumannii;    Pseudomonas aeruginosa;   

DOI  :  10.1016/j.tet.2015.09.019

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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