Eriodictyol as a Potential Candidate Inhibitor of Sortase A Protects Mice From Methicillin-Resistant Staphylococcus aureus-Induced Pneumonia.

Lin Yang,Dacheng Wang,Tiedong Wang,Qianxue Li,Jiaxin Li,Lin Wang,Shisong Jing,Li Wang,Hangqian Yu,Yajing Jin

doi:10.3389/fmicb.2021.635710

Abstract

New anti-infective approaches are urgently needed to control multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA). Sortase A (SrtA) is a membrane-bound cysteine transpeptidase that plays an essential role in the catalysis of covalent anchoring of surface proteins to the cell wall of Staphylococcus aureus (S. aureus). The present study reports identification of a flavonoid, eriodictyol, as a reversible inhibitor of SrtA with an IC50 of 2.229 ± 0.014 μg/mL that can be used as an innovative means to counter both resistance and virulence. The data indicated that eriodictyol inhibited the adhesion of the bacteria to fibrinogen and reduced the formation of biofilms and anchoring of staphylococcal protein A (SpA) on the cell wall. The results of fluorescence quenching experiments demonstrated a strong interaction between eriodictyol and SrtA. Subsequent mechanistic studies revealed that eriodictyol binds to SrtA by interacting with R197 amino acid residue. Importantly, eriodictyol reduced the adhesion-dependent invasion of A549 cells by S. aureus and showed a good therapeutic effect in a model of mouse pneumonia induced by S. aureus. Overall, the results indicated that eriodictyol can attenuate MRSA virulence and prevent the development of resistance by inhibiting SrtA, suggesting that eriodictyol may be a promising lead compound for the control of MRSA infections.

Highlights

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant (MDR) bacterium resistant to methicillin and to other β-lactam antibiotics and members of other antibiotic families (Jaradat et al, 2020)
The recovery of the activity of sortase A (SrtA) was 87.839 ± 1.908% compared with that in the control group after the dilution (Figure 1C). These results indicated that eriodictyol functions as a reversible inhibitor of SrtA, which non-covalently interacts with the active site of SrtA
The minimal inhibitory concentrations (MICs) of eriodictyol against S. aureus USA 300 was greater than 512 μg/mL, and the growth curves of S. aureus USA 300 treated with or without 128 μg/mL eriodictyol showed a similar growth pattern (Figure 1D)

Summary

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant (MDR) bacterium resistant to methicillin and to other β-lactam antibiotics (e.g., oxacillin or cefoxitin) and members of other antibiotic families (Jaradat et al, 2020). The development of novel antibiotics remains an indispensable strategy for the treatment of MRSA infections; the development of new antibiotics is difficult, slow, and far behind the development of drug-resistant strains. Several surface-associated adhesins, such as ClfA/ClfB, fibronectin-binding protein (FnBPs) and collagen adhesin (CAN), are conducive to the pathogenesis of S. aureus infection (Patti et al, 1994; Que et al, 2001; Heying et al, 2007). These essential virulence factors of S. aureus are covalently anchored to the bacterial surface by sortase A (SrtA) (Geoghegan and Foster, 2017)

Objectives

Methods

Results

Conclusion