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Structure–Function Studies on IMD‐0354 Identifies Highly Active Colistin Adjuvants
Author(s) -
Nemeth Ansley M.,
Basak Akash K.,
Weig Alexander W.,
Marrujo Santiana A.,
Barker William T.,
Jania Leigh A.,
Hendricks Tyler A.,
Sullivan Ashley E.,
O'Connor Patrick M.,
Melander Roberta J.,
Koller Beverly H.,
Melander Christian
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900560
Subject(s) - colistin , acinetobacter baumannii , antibiotics , microbiology and biotechnology , multiple drug resistance , bacteria , klebsiella pneumoniae , gram negative bacteria , antibiotic resistance , medicine , biology , escherichia coli , pseudomonas aeruginosa , biochemistry , genetics , gene
Abstract 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 .