Antibiotics (Basel, Switzerland) · 2026
A Cyclic Pentapeptide Inhibits AgrC as a Quorum-Sensing Quenching Agent in Staphylococcus aureus.
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Ai Duiyuan, Duan Huanhuan, Yao Jiahao
Аннотация
BACKGROUND/OBJECTIVES: Staphylococcus aureus virulence is tightly regulated by the agr (accessory gene regulator) quorum-sensing system. Targeting AgrC, the histidine kinase receptor that serves as a core regulator of agr signaling, represents a promising antivirulence strategy that circumvents conventional bactericidal pressure.
METHODS: In this study, structure-based virtual screening using AutoDock Vina was performed, followed by molecular dynamics simulations, to identify potent analogs of known AgrC inhibitors.
RESULTS: A cyclo[Ala-Phe-OLeu-Phe-D-Leu] exhibiting high binding affinity and stable receptor interaction was selected for further evaluation. Antimicrobial susceptibility testing confirmed that the compound did not inhibit bacterial growth. However, at a concentration of 16 µg/mL, it significantly inhibited hemolytic activity with high reproducibility, and the inhibition rate reached 77.60%. Quantitative reverse transcription PCR (RT-qPCR) demonstrated that the compound decreased some key AgrC-mediated genes, including agrC, agrA, saeS, hla, spa, fnbA, and lukS.
CONCLUSIONS: These findings identify a promising cyclic pentapeptide inhibitor of AgrC that effectively attenuates S. aureus virulence without exerting bactericidal pressure. This work provides a valuable lead compound and offers novel insights for the development of advanced, safe, and effective antivirulence therapeutics.
METHODS: In this study, structure-based virtual screening using AutoDock Vina was performed, followed by molecular dynamics simulations, to identify potent analogs of known AgrC inhibitors.
RESULTS: A cyclo[Ala-Phe-OLeu-Phe-D-Leu] exhibiting high binding affinity and stable receptor interaction was selected for further evaluation. Antimicrobial susceptibility testing confirmed that the compound did not inhibit bacterial growth. However, at a concentration of 16 µg/mL, it significantly inhibited hemolytic activity with high reproducibility, and the inhibition rate reached 77.60%. Quantitative reverse transcription PCR (RT-qPCR) demonstrated that the compound decreased some key AgrC-mediated genes, including agrC, agrA, saeS, hla, spa, fnbA, and lukS.
CONCLUSIONS: These findings identify a promising cyclic pentapeptide inhibitor of AgrC that effectively attenuates S. aureus virulence without exerting bactericidal pressure. This work provides a valuable lead compound and offers novel insights for the development of advanced, safe, and effective antivirulence therapeutics.