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

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

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.686864

DOI=10.3389/fmicb.2021.686864

ISSN=1664-302X

ABSTRACT=<p>The evolution and spread of methicillin-resistant <italic>Staphylococcus aureus</italic> (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 <italic>Staphylococcus aureus</italic> (<italic>S. aureus</italic>) 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 IC<sub>50</sub> of 24.53 ± 0.42 μM. Tax did not display toxicity toward mammalian cells or <italic>S. aureus</italic> at a concentration of 200 μM. In addition, Tax attenuated the virulence-related phenotype of SrtA <italic>in vitro</italic> by decreasing the adherence of <italic>S. aureus</italic>, reducing the formation of a biofilm, and anchoring of <italic>S. aureus</italic> 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, <italic>in vivo</italic> 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 <italic>S. aureus</italic> in the lung tissue. The present study indicates that Tax is a useful pioneer compound for the development of novel agents against <italic>S. aureus</italic> infections.</p>