Phytochemical Quorum-Sensing Inhibitors Against Bacterial Pathogens: Mechanisms of Action and Translational...

Antimicrobial resistance is a critical global health challenge, driven by the rapid emergence of multidrug-resistant bacterial pathogens and exacerbated by extensive antibiotic use, which imposes intense selective pressure and disrupts host-associated microbial communities. In this context, quorum sensing (QS), a conserved molecular communication system that coordinates population-level gene regulation, virulence expression, and biofilm development, has emerged as an attractive target for anti-virulence intervention. A growing body of evidence indicates that phytochemicals, such as curcumin, carvacrol, carnosol, eugenol, and chlorogenic acid, can modulate key QS pathways, including acyl-homoserine lactone-, autoinducing peptide-, and LuxS/AI-2-mediated signaling, thereby attenuating pathogenic behaviors at sub-inhibitory concentrations that do not directly impair bacterial viability. Despite this promise, the translational development of phytochemical-based QS inhibitors remains limited. Because QS also regulates cooperative and homeostatic functions in beneficial bacteria, QS-targeted interventions raise concerns about microbiome disruption and ecological imbalance. Furthermore, the literature is marked by substantial methodological heterogeneity, reliance on indirect phenotypic endpoints, limited molecular target validation, and insufficient assessment of toxicity, bioavailability, and pharmacokinetics. The predominance of simplified in vitro models further constrains extrapolation to complex host-associated and polymicrobial environments. This review critically examines the molecular mechanisms underlying phytochemical modulation of bacterial QS, synthesizes pathogen-focused experimental evidence, and evaluates key translational challenges arising from QS conservation, microbiome considerations, and methodological limitations. Addressing these barriers through mechanism-resolved experimentation, standardized evaluation frameworks, and microbiome-aware testing strategies will be essential for advancing phytochemical QS inhibitors toward clinically and industrially relevant anti-virulence applications.