Antibiotic Repurposing: Conjugation of the Gram-Positive Only Peptide Antibiotic Bacitracin to a Bis-Catechol Siderophore Mimetic Imparts Potent Activity against Multi-Drug Resistant Acinetobacter baumannii.

The ongoing emergence of multidrug resistant (MDR) bacteria is a grave concern and is exacerbated by the lack of innovative antibiotics under development. One approach to enhancing antibacterial efficacy is to determine whether derivatives of antibiotics that are normally used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacteria by circumventing permeability barriers and antibiotic deactivation processes. Sideromycins (siderophore-antibiotic conjugates) are recognized by outer membrane protein receptors to initiate the acquisition of essential iron and are actively assimilated by Gram-negative bacteria. Azotochelin is a natural bis-catechol siderophore that is utilized by a broad spectrum of Gram-negative bacteria to sequester iron. Herein we report syntheses of a conjugate of bacitracin with a bis-catechol mimetic of azotochelin. Antibacterial activity assays revealed that coupling of bacitracin, which is only known to be active against Gram-positive bacteria, to the siderophore induced selective potent activity against MDR strains of Gram-negative Acinetobacter baumannii.