Nepetin reduces virulence factors expression by targeting ClpP against MRSA-induced pneumonia infection

ABSTRACT

The resistance of Staphylococcus aureus (S. aureus) to various antibiotics has increased dramatically due to the misuse of antibiotics, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P is a case in hydrolase that regulates the virulence level of S. aureus. Here, we found that nepetin, a small-molecule compound from traditional Chinese herbal flavonoids, effectively inhibits ClpP activity. Nepetin suppressed the virulence of S. aureus and effectively combated the lethal pneumonia caused by MRSA. The results of cellular thermal shift assay showed that nepetin could bind to ClpP and reduce the thermal stability of ClpP, and the K_D value of 602 nM between them was determined using localized surface plasmon resonance. The binding mode of nepetin and ClpP was further investigated by molecular docking, and it was found that Ser-22 and Gln-47 of ClpP residues were found to be involved in the binding of nepetin to ClpP. In conclusion, we determined that nepetin is a ClpP inhibitor and an effective lead compound for the development of a virulence factor-based treatment for MRSA infection.

KEYWORDS:

• MRSA
• anti-virulence
• inhibitor
• caseinolytic peptidase P
• pneumonia

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statements

All data generated during this study are available on request from the corresponding authors.

Supplementary material

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Additional information

Funding

This work was partly supported by a grant from the Science and Technology Development Plan Project (2019) of Jilin Province Science and Technology Department [20190103080JH], “Xinglin Scholar Project” of Changchun University of Chinese Medicine (2019) and“Thirteenth Five-Year Plan” of Science and Technology Project of Education Department of Jilin Province [No. JJKH20200906KJ].