Anti-infective Drug Discovery: Harnessing Multimechanistic Molecules and Emergent Properties to Defeat Pathogenic Complexity

I nfectious diseases remain a formidable challenge to human health throughout the protracted history of host-pathogen warfare.From ancient plagues to emerging pathogens, viruses and bacteria perpetually evolve, manifesting remarkable adaptability and mechanistic complexity.Viruses exhibit even greater complexity: their error-prone replication and hypermutation yield quasi-species swarms that rapidly adapt, 1-4 subverting both immune surveillance and antiviral pharmacotherapy.Among bacteria, the rise of multidrug-resistant (MDR) strains has rendered conventional antimicrobials ineffectual, 5,6 as these organisms orchestrate synergistic resistance mechanisms, altering membrane permeability, elaborating inactivating enzymes, and activating efflux pumps, to dismantle agents with single pharmacodynamic targets.Especially in hospital and clinical settings, MDR strains represent significant risk to patients undergoing minor procedures.Consequently, the traditional "one-target, onedrug" paradigm is increasingly revealing its limitations.The research imperative has to transition toward a "complexityagainst-complexity" strategy, deploying multimechanistic, multilayered therapeutic regimens that systematically disrupt the multidimensional defense networks of pathogens.This work systematically surveys single molecule with multiple mechanisms, multitarget inhibitors, protein degraders, and other cutting-edge approaches to unveil the application potential and research value of molecules with complex mechanisms in anti-infective therapy (Figure 1).