Nepetin reduces virulence factors expression by targeting ClpP against MRSA-induced pneumonia infection
Shisong Jing1, Xinran Ren1,2, Li Wang1
1Clinical Medical College, Changchun University of Chinese Medicine, Changchun, China.
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 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.
Insights
Nepetin, a flavonoid, inhibits Staphylococcus aureus (S. aureus) ClpP activity, suppressing virulence and combating MRSA pneumonia. This offers a new strategy against antibiotic-resistant bacteria.
Area of Science:
- Microbiology
- Pharmacology
- Drug Discovery
Background:
- Antibiotic resistance in Staphylococcus aureus (S. aureus) is a growing global health threat.
- Novel therapeutic targets and anti-infective agents are crucial to overcome resistance.
- Caseinolytic peptidase P (ClpP) is a key regulator of S. aureus virulence.
Purpose of the Study:
- To investigate the potential of nepetin, a flavonoid, as an inhibitor of S. aureus ClpP.
- To evaluate nepetin's efficacy in combating MRSA-induced lethal pneumonia.
- To elucidate the molecular mechanism of nepetin's interaction with ClpP.
Main Methods:
- Cellular thermal shift assay (CETSA) to confirm nepetin-ClpP binding.
- Localized surface plasmon resonance (LSPR) to quantify binding affinity (Kd).
- Molecular docking to determine the binding mode and key residues.
Main Results:
- Nepetin effectively inhibited ClpP activity.
- Nepetin suppressed S. aureus virulence and demonstrated efficacy against MRSA-induced pneumonia.
- CETSA confirmed nepetin binding to ClpP, reducing its thermal stability.
- LSPR determined a Kd value of 602 nM for nepetin-ClpP interaction.
- Molecular docking identified Ser-22 and Gln-47 as key residues involved in binding.
Conclusions:
- Nepetin acts as a ClpP inhibitor.
- Nepetin is a promising lead compound for developing novel anti-virulence therapies against MRSA infections.
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