Harnessing Chemical Diversity to Disarm Bacterial Communication for 25 Years: Natural Products, Repurposed Drugs,...

Quorum sensing, a bacterial communication pathway, has emerged as a promising target for the development of alternative antimicrobial agents in the battle against bacterial resistance. In addition to biological investigations of quorum sensing mechanisms, substantial efforts have been made towards the rational design, synthesis, identification of natural products, and screening of commercial drugs towards this target. There are several individual reviews on the discovery of quorum sensing inhibitors; however, there has yet to be a comprehensive, detailed, and critical review providing a complete overview of the development of novel quorum sensing inhibitors, ranging from natural compounds, peptides, and repurposed drugs to synthetic molecules. This review provides a comprehensive and critical overview of quorum sensing inhibitors, highlighting key advances in their discovery, structure-activity relationships, and mechanisms of action over the past 25 years (2000-2025). It emphasizes several FDA-approved drugs (e.g., azithromycin, ciprofloxacin, and paracetamol), natural compounds (e.g., ajoene, curcumin, quercetin, and carvacrol), peptides, and synthetic libraries that exhibit potent anti-QS and antibiofilm activities against pathogenic bacteria. Furthermore, a systematic structural comparison and potential strategies for developing next-generation therapeutics based on current advancements will be discussed.