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 Mg2+ 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.