In Silico Approaches Targeting Quorum-Sensing Inhibition in Pseudomonas aeruginosa: A Systematic Review

Abstract

Pseudomonas aeruginosa (PA) is a clinically relevant opportunistic pathogen whose persistence and antimicrobial tolerance are largely driven by biofilm formation and quorum-sensing (QS)-regulated virulence. Targeting QS has therefore emerged as an antivirulence strategy that attenuates pathogenicity without exerting strong selective pressure on bacterial growth. This systematic review (2020–2024) analyzes recent advances in the identification of QS inhibitors against PA, emphasizing studies that integrate in silico approaches. Forty-six studies met the inclusion criteria. All employed molecular docking, and 36.9% (n = 17) incorporated molecular dynamics simulations. While valuable for initial detection, these computational predictions have inherent limitations in accurately estimating binding energy and conformational dynamics, requiring empirical validation to confirm actual biological activity. Approximately one-fifth of the studies were exclusively computational, whereas the remainder combined in silico screening with in vitro and, in some cases, in vivo assays. The most frequently investigated QS regulators were LasR, PqsR, and RhlR, alongside additional virulence-associated proteins. The evaluated compounds encompassed phytochemicals, synthetic molecules, nanomaterials and natural product-derived compounds, several of which demonstrated experimental evidence of biofilm attenuation and reduction in QS-regulated virulence factors. Overall, the findings highlight the value of integrating computational and experimental strategies to rationally prioritize antivirulence candidates. However, the intrinsic complexity and redundancy of the QS network suggest that future research should increasingly focus on multitarget approaches and on the exploration of chemically diverse and previously underexplored compound libraries to improve efficacy against PA biofilms.