Repurposing Antibacterial Compounds and Natural Products to Combat Vancomycin-Resistant Enterococci

Abstract

Antibiotic resistance is one of the greatest threats to modern medicine, leaving clinicians with shrinking treatment options for life-threatening infections. Among the most concerning pathogens are vancomycin-resistant Enterococcus (VRE), which causes serious bloodstream, urinary tract, and wound infections, particularly in hospitalized patients. This thesis explores two complementary strategies to address this challenge: natural product discovery and drug repurposing. The first study investigated two drug candidates, CRS3123 and ridinilazole, originally designed to target Clostridioides difficile, for their activity against VRE. Both compounds showed exceptionally low minimum inhibitory concentrations and were bacteriostatic against VRE in vitro. In a Caenorhabditis elegans infection model, treatment with either compound significantly reduced the bacterial burden, demonstrating in vivo efficacy. Safety profiles were favorable, with minimal cytotoxicity and negligible hemolytic activity, highlighting their potential as safe and targeted therapies against VRE infections. In the second study, I evaluated maslinic acid, a naturally occurring plant-derived triterpene, for its potential against VRE. Maslinic acid inhibited bacterial growth and significantly reduced biofilm formation, an important mechanism that allows VRE to persist in hospital environments and resist treatment. Importantly, it showed low cytotoxicity in mammalian cells, indicating promise as a safe therapeutic scaffold. Together, these studies highlight the value of diverse approaches to antibiotic discovery. Natural compounds like maslinic acid expand chemical diversity, while repurposing candidates such as CRS3123 and ridinilazole accelerate potential clinical application. This thesis provides new insights into strategies for combating multidrug-resistant Enterococcus, a pathogen of urgent medical concern.