Bioorganic strategies for quorum sensing inhibition: disrupting biofilms and virulence in drug-resistant pathogens.
The escalating global crisis of antimicrobial resistance (AMR) poses a severe threat to public health, with bacterial biofilms and virulence factors exacerbating treatment failures in drug-resistant pathogens. Quorum sensing (QS), a density-dependent communication system, orchestrates biofilm formation, virulence expression, and resistance mechanisms in clinically relevant bacteria, including Pseudomonas aeruginosa, Staphylococcus aureus, and other pathogenic bacteria. Unlike conventional antibiotics, which exert selective pressure that can lead to resistance, QS inhibition offers a promising anti-virulence strategy by attenuating pathogenicity without directly killing bacteria. This review focuses on bioorganic approaches to QS disruption, encompassing natural products, synthetic analogues, hybrid phytocompound-nanoparticle conjugates, and metal-organic frameworks (MOFs). Key sections explore QS systems in Gram-negative and Gram-positive pathogens; molecular mechanisms of inhibition, including autoinducer synthesis blockade, receptor antagonism, and enzymatic degradation; structure-activity relationships (SAR), with emphasis on pharmacophores such as hydroxyl groups and α,β-unsaturated carbonyls; and evidence of biofilm and virulence attenuation in drug-resistant strains from in vitro, ex vivo, and in vivo studies. Synergistic effects with sub-MIC antibiotics are also highlighted, alongside challenges related to bioavailability, toxicity, and regulatory hurdles. Prospects include bioorthogonal probes for QS tracking, machine learning-aided design of next-generation inhibitors, nanoparticle-mediated targeted delivery, and emerging preclinical candidates. By leveraging advances in bioorganic chemistry, QS inhibition holds substantial translational potential for the management of AMR-driven infections and may redefine future therapeutic paradigms in infectious disease control.