Inhibitory Effect of Amentoflavone on the Virulence of MRSA by Targeting ClpP

Gele T. Kong X. Zhang Q. Song W. Guo J. Hamidi P. Mani K. Han S. Zhao X. Chen J. Zhang C. Abduldayevna A.A. Li Q.
October 2025 John Wiley and Sons Inc

Journal of Cellular and Molecular Medicine
2025 #29 Issue 20

Methicillin-resistant Staphylococcus aureus (MRSA) poses significant therapeutic challenges due to its global spread and virulence. Targeting the critical virulence regulator ClpP presents a promising antivirulence strategy. This study investigated AMFs mechanism against MRSA through molecular dynamics simulations, FRET and TSA. Phenotypic analyses revealed AMFs inhibition of MRSA haemolytic activity (72% reduction) and biofilm formation (58% decrease) without affecting bacterial growth. Molecular docking identified key AMF–ClpP interaction sites (ARG-171, ASP-170, ASP-172), validated via CETSA. AMF reduced transcription of critical virulence genes (hla, psmα) by 3.8-fold and inhibited ClpP enzymatic activity by 65%. Cellular studies demonstrated AMFs protection of A549 lung cells from MRSA infection (82% viability vs. 43% control). In murine pneumonia models, AMF treatment enhanced survival rates from 20% to 75% while reducing proinflammatory cytokines (IL-6, TNF-α) by 60%–70%. Histopathological analysis showed significant mitigation of lung tissue damage. These findings establish AMF as a potent ClpP inhibitor that attenuates MRSA virulence through dual mechanisms: suppression of toxin production and biofilm formation. The compounds therapeutic potential stems from its ability to disarm pathogenic mechanisms while maintaining commensal microbiota integrity. This study provides proof-of-concept for antivirulence strategies targeting ClpP, offering a promising alternative to traditional antibiotics against MRSA infections.

antivirulence strategies , ClpP , MRSA , natural compound

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Changchun University of Chinese Medicine, Changchun, China
Endocrinology Department, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
Xinjiang Altay Regional Hospital of Traditional Chinese Medicine, Altay, China
The University of Queensland, St Lucia, QLD, Australia
Astana Medical University, Astana, Kazakhstan

Changchun University of Chinese Medicine
Endocrinology Department
Research Center of Traditional Chinese Medicine
Xinjiang Altay Regional Hospital of Traditional Chinese Medicine
The University of Queensland
Astana Medical University

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