Niacin-Cholic Acid-Peptide Conjugate Act as a Potential Antibiotic Adjuvant to Mitigate Polymicrobial Infections Caused by Gram-Negative Pathogens

Polymicrobial wound infections caused by Gram-negative bacteria and associated inflammation are challenging to manage, as many antibiotics do not work against these infections. Utilizing adjuvants to repurpose the existing antibiotics for mitigating microbial infections presents an alternative therapeutic strategy. We designed and developed a niacin-cholic acid-peptide conjugate (<b>1</b>) to rejuvenate the therapeutic efficacy of macrolide antibiotics against Gram-negative pathogens. We conjugated niacin with anti-inflammatory properties at the carboxyl terminal of the cholic acid and dipeptide (glycine-valine) at the three hydroxyl terminals of cholic acid to obtain the amphiphile <b>1</b>. Our findings demonstrated that amphiphile <b>1</b> serves as a microbial membrane disruptor that facilitates the entry of erythromycin (ERY) in bacterial cells. The combination of amphiphile <b>1</b> and ERY is bactericidal and can effectively eliminate monomicrobial and polymicrobial Gram-negative bacterial biofilms. We further demonstrated the antibacterial effectiveness of combining <b>1</b> and ERY against monomicrobial and polymicrobial wound infections. Together, these findings indicate that amphiphile <b>1</b> revitalizes the remedial efficacy of ERY against Gram-negative bacteria.