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Abstract
Infections caused by multi-drug 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
report, 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 .