Sequential eradication of bacterial persisters: integrating phytochemical pharmacology with microenvironment-responsive delivery strategies.

Bacterial persister cells within extracellular polymeric substance (EPS) matrices drive antimicrobial tolerance and chronic infection relapse. Conventional bactericidal agents remain fundamentally inadequate against these dormant subpopulations due to their reliance on active cellular metabolism. This review proposes a mechanistically driven, multi-phase sequential strategy-comprising barrier disruption, metabolic resuscitation, and terminal eradication-executed via highly purified, plant-derived natural products and advanced delivery systems. We synthesize recent pharmacological evidence regarding the anti-biofilm mechanisms of these active monomers and their integration with microenvironment-responsive strategies. A three-phase framework is delineated. Phase I utilizes epigallocatechin gallate (EGCG) and baicalin to physically degrade the EPS architecture and antagonize quorum sensing networks. Phase II employs Astragalus polysaccharides (APS) and exogenous metabolites to restore microbicidal host immunity and reactivate bacterial central carbon metabolism. Phase III leverages this reactivated state, utilizing berberine and shikonin to induce lethal reactive oxygen species (ROS) accumulation and terminal respiratory arrest. To resolve the pharmacokinetic limitations of these phytochemicals, we conceptualize integrating stimuli-responsive delivery systems for chronologically programmed drug release triggered by biofilm microenvironmental gradients. Ultimately, this sequential "disrupt-awaken-kill" strategy offers a potent framework to eradicate recalcitrant persisters, though translating these multi-component therapies into clinical practice requires overcoming existing manufacturing and regulatory complexities.