Abstract
Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity in vivo. We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKβ in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii-induced peritonitis. These novel adjuvants show low toxicity in vivo, significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection.