Taxifolin, an Inhibitor of Sortase A, Interferes With the Adhesion of Methicillin-Resistant Staphylococcal aureus.

Li Wang,Qianxue Li,Kai Wang,Dacheng Wang,Han Qu,Shisong Jing,Guangming Wang,Shuhan Guan,Liyan Su

doi:10.3389/fmicb.2021.686864

Abstract

The evolution and spread of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant hidden risk to human public health. The majority of antibiotics used clinically have become mostly ineffective, and so the development of novel anti-infection strategies is urgently required. Since Staphylococcus aureus (S. aureus) cysteine transpeptidase sortase A (SrtA) mediates the surface-anchoring of proteins to its surface, compounds that inhibit SrtA are considered potential antivirulence treatments. Herein, we report on the efficacy of the potent SrtA inhibitor taxifolin (Tax), a flavonoid compound isolated from Chinese herbs. It was able to reversibly block the activity of SrtA with an IC50 of 24.53 ± 0.42 μM. Tax did not display toxicity toward mammalian cells or S. aureus at a concentration of 200 μM. In addition, Tax attenuated the virulence-related phenotype of SrtA in vitro by decreasing the adherence of S. aureus, reducing the formation of a biofilm, and anchoring of S. aureus protein A on its cell wall. The mechanism of the SrtA-Tax interaction was determined using a localized surface plasmon resonance assay. Subsequent mechanistic studies confirmed that Asp-170 and Gln-172 were the principal sites on SrtA with which it binds to Tax. Importantly, in vivo experiments demonstrated that Tax protects mice against pneumonia induced by lethal doses of MRSA, significantly improving their survival rate and reducing the number of viable S. aureus in the lung tissue. The present study indicates that Tax is a useful pioneer compound for the development of novel agents against S. aureus infections.

Highlights

There is currently major worldwide concern about the continuous emergence of multidrugresistant bacterial pathogens
The flavonoid Tax was found to display excellent inhibitory properties against S. aureus sortase A (SrtA), with an IC50 value of 24.53 ± 0.42 μM (Figures 1A,B). This suggests that Tax is a relatively strong inhibitor of SrtA, compared with previously reported inhibitory small molecules (Oh et al, 2004; Chenna et al, 2010)
Recent studies have shown that the proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients is increasing, leading to significant incidence rate and mortality (Iwata et al, 2020)

Summary

Introduction

There is currently major worldwide concern about the continuous emergence of multidrugresistant bacterial pathogens. Staphylococcus aureus (S. aureus) is recognized as an important cause of disease worldwide. It is capable of inducing a variety of serious diseases that endanger human health, from mild skin and soft tissue infection to fatal invasive infections such as septicemia. The considerable selective pressure and improper use of antibiotics have resulted in the emergence, prevalence, and spread of drugresistant strains of bacteria (Liu et al, 2019; Wu et al, 2019). As strains of methicillin-resistant Staphylococcus aureus (MRSA) with little sensitivity to conventional antibiotics have become prevalent (Prestinaci et al, 2015), treatments for MRSA infection have become more challenging for clinicians, who require new strategies to provide effective therapeutic options against complicated S. aureus infections (Kali, 2015; Galar et al, 2019)

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Conclusion