On-demand recession of quaternary ammonium biocides for combating multidrug resistance

Antibiotic misuse is a key driver of antimicrobial resistance, but extensive use and prolonged environmental persistance of disinfectants like quaternary ammonium compounds (QACs), poses an urgent and underappreciated threat. Conventional QACs accumulate at sub-inhibitory concentrations (sub-MICs), accelerating multidrug resistance (MDR) in bacteria via sustained selection pressure. We introduce R-substituted silaketal-bridged QACs (RSBQs), which feature acid-cleavable linkages that enable controllable hydrolysis from bactericidal to non-toxic states. By modulating the R-substituents and environmental conditions, degradation half-lives range from 12 h to 6 days, reducing selection pressure before resistance establishes. Even at sub-MICs, partially degraded RSBQs such as ethyl-substituted SBQ (Et-SBQ) and n-propyl-substituted SBQ (nPr-SBQ), exhibit dual resistance-suppression, including downregulation of resistance gene expression and inhibition of efflux pump activity. By resensitizing multidrug-resistant bacteria to antibiotics, Et-SBQ synergized with ciprofloxacin to accelerate wound healing in mice. This strategy combines potent antibacterial activity, environmental degradability, and resistance suppression, offering a promising MDR solution.