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Small molecule adjuvants that enhance the activity of otherwise gram\u2010positive selective antibiotics against gram\u2010negative bacteria have the potential to expand current treatment options. We have previously reported adjuvants based upon a 2\u2010aminoimidazole (2\u2010AI) scaffold that potentiate macrolide antibiotics against several gram\u2010negative pathogens. Herein, we report the discovery and structure\u2010activity relationship (SAR) investigation of an additional class of macrolide adjuvants based upon a 2\u2010aminobenzimidazole (2\u2010ABI) scaffold. The lead compound lowers the minimum inhibitory concentration (MIC) of clarithromycin (CLR) from 512 to 2\u2005\u03bcg\/mL at 30\u2005\u03bcM against <jats:italic>Klebsiella pneumoniae<\/jats:italic> 2146, and from 32 to 2\u2005\u03bcg\/mL at 5\u2005\u03bcM, against <jats:italic>Acinetobacter baumannii<\/jats:italic> 5075. Preliminary investigation into the mechanism of action suggests that the compounds are binding to lipopolysaccharide (LPS) in <jats:italic>K.\u2005pneumoniae<\/jats:italic>, and modulating lipooligosaccharide (LOS) biosynthesis, assembly, or transport in <jats:italic>A.\u2005baumannii<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/cbic.202400127","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T13:03:21Z","timestamp":1709816601000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of a 2\u2010Aminobenzimidazole Scaffold that Potentiates Gram\u2010Positive Selective Antibiotics Against Gram\u2010Negative Bacteria"],"prefix":"10.1002","volume":"25","author":[{"given":"Ansley M.","family":"Nemeth","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Notre Dame  Notre Dame IN-46556 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