Glycyrrhizin (GLY) and glycyrrhetinic acid (GA) as potential multi-target antimicrobials: mechanisms, biofilm disruption, and synergy against drug-resistant pathogens.

Antimicrobial resistance (AMR) is a major global health challenge of the 21 st century, driven by multidrug-resistant pathogens, persistent biofilm-associated infections, and a dwindling pipeline of new antibiotics. These limitations have renewed interest in natural products with multi-target antimicrobial activity. Glycyrrhiza glabra, a medicinal herb, produces glycyrrhizin (GLY), a triterpenoid saponin, and its active metabolite, glycyrrhetinic acid (GA), both of which exhibit antibacterial, antiviral, and antibiofilm activity. These compounds act through coordinated mechanisms, including disrupting microbial membranes, inhibiting metabolic pathways, modulating efflux systems, suppressing biofilm structure, and regulating host inflammatory responses. Their ability to enhance antibiotic efficacy further supports their role as adjunctive therapeutic agents. This review critically synthesizes current knowledge on the chemical properties, molecular mechanisms of action, pathogen-specific activity, biofilm interference, pharmacokinetics, safety considerations, and translational potential of these triterpenoids. Collectively, the available data could position G. glabra-derived triterpenoids as promising adjunctive candidates for next-generation multi-target antimicrobials.