Structure-activity relationship and membrane-targeting mechanisms of shikimate-related metabolites against Gram-positive and Gram-negative bacteria

AIMS: The rise of antibiotic-resistant bacteria has intensified the search for novel antimicrobials. In this context, shikimic acid is a versatile scaffold widely used as a precursor to bioactive compounds and drugs. This study screened the antimicrobial activity and underlying mechanism of 18 shikimate-related metabolites against Escherichia coli and Staphylococcus epidermidis. METHODS AND RESULTS: The antimicrobial activity of the metabolites was initially evaluated by determining their minimum inhibitory concentrations (MICs). Caffeic acid, p-coumaric acid, and α-methylhydrocinnamic acid exhibited the lowest MIC values and were selected for further evaluation of bacterial inactivation kinetics and effects on bacterial cell surface and membrane integrity. α-Methylhydrocinnamic acid showed rapid antibacterial effects with maximum reductions of 3.2 and 3.9 log CFU.mL-1 for E. coli and S. epidermidis, respectively. Caffeic acid and p-coumaric acid were less effective, particularly against E. coli, where antimicrobial activity plateaued over time. In E. coli, caffeic acid and p-coumaric acid increased surface hydrophilicity by 15% and 46%, respectively, whereas in S. epidermidis, p-coumaric acid and α-methylhydrocinnamic acid reduced hydrophilicity by 55% and 67%. Zeta potential measurements showed less negative surface charges in E. coli following treatment with p-coumaric acid and α-methylhydrocinnamic acid, whereas in S. epidermidis, α-methylhydrocinnamic acid increased surface charge. Additionally, α-methylhydrocinnamic acid caused pronounced membrane disruption, with bacterial cells with damaged membranes reaching 70% in E. coli and 90% in S. epidermidis, alongside a 54% increase in K⁺ leakage for E. coli. CONCLUSIONS: These findings highlight the potential of cinnamic acid derivatives, particularly α-methylhydrocinnamic acid, may have potential for further investigation as antibacterial compounds or as adjuncts to conventional antimicrobial strategies.