Dimeric Cholic Acid Peptide Conjugates Act as Effective Antibiotic Adjuvants against Multidrug Resistance (MDR) Gram‐Negative Bacterial Infections

Abstract Macrolides, glycopeptides, lipopeptides, and oxazolidinones class of antibiotics are used only for Gram‐positive bacteria, and are ineffective against Gram‐negative bacteria due to inability of these antibiotics to cross the Gram‐negative bacterial membranes. Here, dimeric cholic acid peptide conjugates as effective adjuvants that allow penetration of erythromycin across Gram‐negative bacteria are presented, making it effective antimicrobial. Here, it is shown that synthesized dimers 2 and 3, having tetramethylene and pentamethylene spacers respectively between cholic acid‐triglycine conjugates, in combination with erythromycin cause synergistic antimicrobial effect against Gram‐negative bacteria. Biochemical studies reveal that dimer 3 causes outer and inner membrane permeabilization by interacting with lipopolysaccharide and displacing Mg 2+ ions, thereby allowing the erythromycin to cross bacterial membranes. Dimer 3 in combination with erythromycin can clear the preformed biofilms of E. coli and P. aeruginosa effectively. It is further demonstrated that combination of dimer 3 and erythromycin can clear wound infections of E. coli and P. aeruginosa . Additionally, activities against multidrug resistant clinical strains of E. coli and P. aeruginosa witness that combination of dimer 3 and erythromycin is an ideal combination to mitigate drug‐resistant infections.