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 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 effect, thereby minimizing the likelihood of resistance evolution.

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria

“…Both compounds were previously disclosed by our group as potent modulators of colistin resistance in isolates with endogenous colistin resistance. 11 The colistin MIC of each strain was determined in the presence of either 30 or 15 μM adjuvant. At 30 μM, we observed reductions of 16 to >2,048-fold with compound 1 and 8 to 512-fold with compound 2 (Table 2).…”

A Whole-Cell Screen Identifies Small Bioactives That Synergize with Polymyxin and Exhibit Antimicrobial Activities against Multidrug-Resistant Bacteria

“…Recent repurposed pharmaceuticals have been experimentally used with varying success to potentiate the activity of polymyxins; however, none of these has been demonstrated to be effective against all of the ESKAPE pathogens (28,46,47,49,71,73,(75)(76)(77)(78)(79)(80)(81). New antimicrobials have also been identified and shown to be effective against polymyxin-resistant bacterial strains, which raises the hope that new FDA-approved antibiotics may emerge in the future (30)(31)(32)(33)(34)(35)(82)(83)(84)(85)(86)(87)(88). In the interim, other groups have pursued developing polymyxin-sparing regimes, such as pentamidine, in order to avoid the clinical use of polymyxins and circumvent their inherent toxicity (29).…”

Identification of Anti‐Mycobacterial Biofilm Agents Based on the 2‐Aminoimidazole Scaffold

“…Following re-synthesis of compound 1 for this study,I C 50 and EC 50 values of 10.4 and 80.5 mm,r espectively,w ere obtained ( Table 1). The MIC of compound 1 is 100 mm.W enext screeneds everalp reviously reporteds ubstituted 2-aminoimidazoles [18] for the ability to inhibit and disperse M. smegmatis biofilms. Of these, none of the compoundst hat contain substituted phenyl moieties at the 5-position of the 2-AI ring inhibited or dispersed biofilms to any significant degree (compounds S1-S4 Table S1 in the Supporting Information).…”