Work

A Cyclic Pentapeptide Inhibits AgrC as a Quorum-Sensing Quenching Agent in Staphylococcus aureus

Year: 2026

Type: article

Abstract: 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.

Source: Antibiotics

DOI: 10.3390/antibiotics15020213

Authors: Duiyuan Ai, Huanhuan Duan, Jiahao Yao

Institution: Gansu Agricultural University

Language: English

Topic: Bacterial biofilms and quorum sensing

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499