Structure–Function Studies on IMD‐0354 Identifies Highly Active Colistin Adjuvants

Infections caused by multidrug‐resistant (MDR) bacteria, particularly Gram‐negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last‐resort antibiotic colistin; however, colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram‐negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics. We recently disclosed that the known IKK‐β inhibitor IMD‐0354 potently suppresses colistin resistance in several Gram‐negative strains. In this study, we explore the structure–activity relationship (SAR) between the IMD‐0354 scaffold and colistin resistance suppression, and identify several compounds with more potent activity than the parent against highly colistin‐resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae. The breaking point of drug resistance: We report a structure–activity relationship (SAR) study on the recently identified colistin adjuvant IMD‐0354, and describe several compounds with more potent activity than the parent, including one analogue that suppresses the colistin minimum inhibitory concentration (MIC) below the breakpoint level against a highly resistant strain of Klebsiella pneumoniae at 250 nM.