title: Second Generation Modifiers of Colistin Resistance Show Enhanced Activity and Lower Inherent Toxicity.
abstract: We recently reported a 2-aminoimidazole-based antibiotic adjuvant that reverses colistin resistance in two species of Gram-negative bacteria. Mechanistic studies inAcinetobacter baumanniidemonstrated 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 effect, thereby minimizing the likelihood of resistance evolution.
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8024.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Brackett
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8024.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Furlani
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8024.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Anderson
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8024.
authors.forename: Aparna
authors.initials: A
authors.lastname: Krishnamurthy
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8024.
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Melander
authors.affiliation: Departments of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Moskowitz
authors.affiliation: Department of Microbial Pathogenesis, University of Maryland - Baltimore, Baltimore MD 21201.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Ernst
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8024.
authors.forename: Christian
authors.initials: C
authors.lastname: Melander
keywords: 2-aminoimidazole; Acinetobacter baumannii; Antibiotic adjuvant; ESKAPE pathogens; Pseudomonas aeruginosa; colistin