Cholic Acid-Peptide Conjugates as Potent Antimicrobials against Interkingdom Polymicrobial Biofilms

Abstract

Interkingdom polymicrobial biofilms formed by Gram-positive <i>Staphylococcus aureus</i> and <i>Candida albicans</i> pose serious threats of chronic systemic infections due to the absence of any common therapeutic target for their elimination. Herein, we present the structure-activity relationship (SAR) of membrane-targeting cholic acid-peptide conjugates (CAPs) against Gram-positive bacterial and fungal strains. Structure-activity investigations validated by mechanistic studies revealed that valine-glycine dipeptide-derived CAP 3 was the most effective broad-spectrum antimicrobial against <i>S. aureus</i> and <i>C. albicans</i> CAP 3 was able to degrade the preformed single-species and polymicrobial biofilms formed by <i>S. aureus</i> and <i>C. albicans</i>, and CAP 3-coated materials prevented the formation of biofilms. Murine wound and catheter infection models further confirmed the equally potent bactericidal and fungicidal effect of CAP 3 against bacterial, fungal, and polymicrobial infections. Taken together, these results demonstrate that CAPs, as potential broad-spectrum antimicrobials, can effectively clear the frequently encountered polymicrobial infections and can be fine-tuned further for future applications.