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

Abstract

AbstractMacrolides, 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 dimers2and3,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 dimer3causes outer and inner membrane permeabilization by interacting with lipopolysaccharide and displacing Mg2+ions, thereby allowing the erythromycin to cross bacterial membranes. Dimer3in combination with erythromycin can clear the preformed biofilms ofE. coliandP. aeruginosaeffectively. It is further demonstrated that combination of dimer3and erythromycin can clear wound infections ofE. coliandP. aeruginosa. Additionally, activities against multidrug resistant clinical strains ofE. coliandP. aeruginosawitness that combination of dimer3and erythromycin is an ideal combination to mitigate drug‐resistant infections.