Advances in quorum-sensing inhibitors as novel therapeutic targets

The growing antimicrobial resistance (AMR) has again prompted consideration of therapeutic strategies that reduce bacterial virulence rather than directly impairing viability. Quorum sensing (QS) is a density-dependent signaling network that controls the production of virulence factors, biofilm formation, metabolic reorganization, and interspecies communication in most clinically important pathogens. Quorum-sensing inhibitors (QSIs) target such coordinated behaviors by blocking autoinducer biosynthesis, signal degradation, receptor activation, or transcriptional networks downstream of these receptors. Naturally occurring, synthetic small molecules; synthetic, engineered peptide-based; and quorum-quenching-designed QSIs have been shown to suppress virulence gene expression and biofilm architecture in preclinical models of Pseudomonas aeruginosa, Staphylococcus aureus, and Vibrio species. QS disruption in the chosen systems increases susceptibility to antibiotics and alters the nature of interactions during infection, with no direct bactericidal effect. Nevertheless, the hurdles to translational progress remain considerable, including signaling redundancy, context-dependent evolution of resistance, pharmacokinetic variability, and the lack of signaling pathways specific to anti-virulence agents. Explaining the therapeutic window, resistance profile, and additive value of QS inhibition, and how to combine it with current antimicrobials, will determine whether such a strategy can play a significant role in the development of future generations of anti-infective agents.