Overcoming Nanosilver\nResistance: Resensitizing Bacteria\nand Targeting Evolutionary Mechanisms

The rapid spread of antimicrobial resistance poses a\ncritical threat\nto global health and the environment. Antimicrobial nanomaterials,\nincluding silver nanoparticles (AgNPs), are being explored as innovative\nsolutions; however, the emergence of nanoresistance challenges their\neffectiveness. Understanding resistance mechanisms is essential for\ndeveloping antievolutionary strategies. AgNPs exhibit diverse resistance\nmechanisms, and our findings reveal a dynamic transition between these\nmechanisms: from flagellin-mediated AgNP precipitation (state I) to\nactivation of the copper efflux pump (CusCFBA) system (state II).\nWe designed targeted physicochemical interventions to counteract these\nmechanisms. Energy supply blocking was effective for state I, while\nfor state II, neutralizing intracellular acidic pH significantly reduced\nresistance. These strategies reduced nanoresistance/tolerance by up\nto 10,000-fold. Additionally, resistance evolution can be completely\nhalted by disrupting the energy supply using carbonyl cyanide 3-chlorophenylhydrazone\nand overactivating sigma E, one of the key envelope stress regulators\nthat govern resistance transitions. Our findings provide practical\nstrategies to overcome nanoresistance, offering a groundbreaking approach\nto enhance nanoantimicrobials’ efficacy in medical therapies\nand combat resistance evolution.