Abstract
Antibiotic resistance has become increasingly prevalent over the past few decades, and this combined with a dearth in the development of new classes of antibiotics to treat multidrug resistant Gram-negative infections has led to a significant global health problem and the increased usage of colistin as the last resort antibiotic. Colistin, however, presents dose dependent toxicity in the clinic. One potential approach to combatting this problem is the use of an antibiotic adjuvant, a compound that is nontoxic to the bacteria that enhances the potency of colistin and ultimately allows for reducing dosing. Herein, we present a new urea-containing class of 2-aminoimidazole-based adjuvants that potentiates colistin activity against colistin-sensitive Acinetobacter baumannii. Lead compounds enabled 1000-fold reduction in the minimum inhibitory concentration of colistin in vitro and showed efficacy in a Galleria mellonella infection model, representing the first step toward validating the potential of employing these adjuvants to lower colistin dosage.