pH-Responsive Delivery of D-Amino Acids by Pillar[5]arene for Enhanced Antibiofilm and Antibacterial Activities

Abstract Biofilms are a promising target to combat antibiotic resistance, but D-amino acids require high doses for biofilm inhibition. To overcome this, a novel antibiofilm agent was designed by anchoring D-amino acids onto the pillar[5]arene scaffold via acid-labile imine linkages. Pillar[5]arenes functionalized with D-amino acids showed enhanced antibiofilm activities compared to free D-amino acids, attributed to the localized release of D-amino acids within biofilms. Moreover, synergy was observed when conventional antibiotics ERY and TET were combined with PAY10. Benefiting from biofilm disruption, the combined treatment exposed bacteria to antibiotics, thereby improving MRSA susceptibility. In addition, the pillar[5]arene derivatives exhibited no cytotoxicity at the tested concentrations. Lastly, the expression levels of AgrA and dltD genes in MRSA were downregulated after treatment with PAY10. This revealed that the compound reduced biofilm mass by quenching quorum-sensing signals and repressing the production of extracellular polymeric substances.