Identification of a 2-Aminobenzimidazole Scaffold that Potentiates Gram-Positive Selective Antibiotics Against Gram-Negative Bacteria

The development of novel therapeutic approaches is crucial in the fight against multi-drug resistant (MDR) bacteria, particularly gram-negative species. Small molecule adjuvants that enhance the activity of otherwise gram-positive selective antibiotics against gram-negative bacteria have the potential to expand current treatment options. We have previously reported adjuvants based upon a 2-aminoimidazole (2-AI) scaffold that potentiate macrolide antibiotics against several gram-negative pathogens. Herein, we report the discovery and structure-activity relationship (SAR) investigation of an additional class of macrolide adjuvants based upon a 2-aminobenzimidazole (2-ABI) scaffold. The lead compound lowers the minimum inhibitory concentration (MIC) of clarithromycin (CLR) from 512 to 2 mu g/mL at 30 mu M against Klebsiella pneumoniae 2146, and from 32 to 2 mu g/mL at 5 mu M, against Acinetobacter baumannii 5075. Preliminary investigation into the mechanism of action suggests that the compounds are binding to lipopolysaccharide (LPS) in K. pneumoniae, and modulating lipooligosaccharide (LOS) biosynthesis, assembly, or transport in A. baumannii. Small molecule adjuvants have the potential to expand the spectrum of gram-positive selective antibiotics to encompass gram-negative bacteria. We identifiy a series of 2-aminobenzimidazole (2-ABI) macrolide adjuvants with activity against Acinetobacter baumannii and Klebsiella pneumoniae. Preliminary mechanism of action studies suggests that adjuvants bind to lipopolysaccharide in K. pneumoniae, and modulate lipooligosaccharide biosynthesis, assembly, or transport in A. baumannii. image