Hijacking the signal: a critical evaluation of quorum sensing inhibitors as a next-generation approach against Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is an opportunistic, Gram-positive pathogen that forms significant clinical challenges due to its multidrug-resistant mechanisms, diverse virulence factors, and robust biofilm-forming capacity. One of the main drivers of antimicrobial resistance (AMR) is the selective pressure exerted by antibiotic use, necessitating alternative therapeutic strategies. Among these, quorum-sensing inhibitors (QSIs) have emerged as promising candidates for disrupting bacterial communication and reducing virulence without compromising bacterial viability. This review focuses on targeting S. aureus communication systems, particularly the accessory gene regulator (agr) quorum-sensing system. We first provide an overview of biofilm development strategies in S. aureus, define bacterial communication networks, and discuss the advantages and limitations of targeting these systems as a strategy for virulence attenuation. We also explore the interplay between regulatory systems within biofilms and how they influence each stage of biofilm maturation. The agr system comprises a network of proteins that can be selectively targeted to disrupt its signaling cascade. Potential intervention points include (1) obstruction of autoinducing peptide (AIP) synthesis, (2) degradation of preformed AIPs, (3) competitive inhibition or modification of the histidine kinase receptor AgrC, and (4) interference with downstream effectors such as AgrA and RNAIII. Given that the agr system primarily operates in the later stages of biofilm development, facilitating biofilm dispersal and upregulating virulence genes, QSIs alone may attenuate virulence yet risk persistent biofilm-associated infections. Accordingly, we emphasize the importance of combining QSIs with biofilm-disrupting or eradicating agents to reduce both biofilm formation and virulence, while minimizing the risk of resistance emergence. Future research should focus on optimizing such combinatorial strategies, evaluating in vivo efficacy, and ensuring safety and minimal off-target effects to facilitate clinical translation of QSIs as viable anti-virulence therapeutics against S. aureus infections.