Myricetin protects mice against MRSA-related lethal pneumonia by targeting ClpP.

Abstract

Methicillin-resistant Staphylococcus aureus is one of the leading causes of community and nosocomial infections, which has created the urgent need for innovative anti-infective agents to control MRSA-associated infections. A conserved serine protease, caseinolytic peptidase P (ClpP) in Staphylococcus aureus is highly associated with pathogenicity and has been claimed to be a novel antimicrobial target. We aim to search suitable inhibitors of ClpP to attenuate the virulence of MRSA and combat their infections in vivo. Over 500 natural compounds were pre-screened via fluorescence resonance energy transfer using the Suc-LY-AMC substrate. The binding of myricetin to ClpP was determined and the mechanism of action was elucidated by thermal shift assay, surface plasmon resonance, and molecular dynamics simulations. The therapeutic effects of myricetin on S. aureus infection were further investigated using a S. aureus-induced pneumonia model. We revealed that myricetin could effectively block the activity of ClpP without disturbing the growth of the bacteria and the Gln-47 and Met-31 residues were necessary for myricetin binding to ClpP. Importantly, myricetin attenuated the pathogenicity of S. aureus in vivo, while improving the efficacy of the traditional antibiotic oxacillin against MRSA infection and protecting mice from fatal lung infections caused by MRSA. These findings indicate that myricetin has the potential to be applied in the pharmaceutical industry as a promising therapeutic agent.

• Authors: Shisong Jing, Li Wang, Tiedong Wang, Lianghai Fan, Lin Chen, Hua Xiang, Yan Shi, Dacheng Wang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 192 Pg. 114753 (10 2021) ISSN: 1873-2968 [Electronic] England
• PMID: 34474040 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Flavonoids
• myricetin
• CLPP protein, mouse
• Endopeptidase Clp

Topics

• Animals
• Dose-Response Relationship, Drug
• Drug Delivery Systems (methods)
• Endopeptidase Clp (metabolism)
• Female
• Flavonoids (administration & dosage, metabolism)
• Hep G2 Cells
• Humans
• Methicillin-Resistant Staphylococcus aureus (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Pneumonia, Bacterial (metabolism, prevention & control)
• Staphylococcal Infections (metabolism, prevention & control)