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Echinacoside, a promising sortase A inhibitor, combined with vancomycin against murine models of MRSA-induced pneumonia

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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium responsible for a range of severe infections, such as skin infections, bacteremia, and pneumonia. Due to its antibiotic-resistant nature, current research focuses on targeting its virulence factors. Sortase A (SrtA) is a transpeptidase that anchors surface proteins to the bacterial cell wall and is involved in adhesion and invasion to host cells. Through fluorescence resonance energy transfer (FRET), we identified echinacoside (ECH), a natural polyphenol, as a potential SrtA inhibitor with an IC50 of 38.42 μM in vitro. It was demonstrated that ECH inhibited SrtA-mediated S. aureus fibrinogen binding, surface protein A anchoring, and biofilm formation. The fluorescence quenching assay determined the binding mode of ECH to SrtA and calculated the KA-binding constant of 3.09 × 105 L/mol, demonstrating the direct interaction between the two molecules. Molecular dynamics simulations revealed that ECH–SrtA interactions occurred primarily at the binding sites of A92G, A104G, V168A, G192A, and R197A. Importantly, the combination of ECH and vancomycin offered protection against murine models of MRSA-induced pneumonia. Therefore, ECH may serve as a potential antivirulence agent against S. aureus infections, either alone or in combination with vancomycin.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was partly supported by a grant from the Science and Technology Development Plan Project (2019) of the Jilin Province Science and Technology Department (20190103080JH), “Xinglin Scholar Project” of Changchun University of Chinese Medicine (2019) and “Thirteenth Five-Year Plan” of Science and Technology Project of Education Department of Jilin Province (No. JJKH20200906KJ).

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Authors and Affiliations

  1. Changchun University of Chinese Medicine, Changchun, 130117, China

    Tao Jiang, Dai Yuan, Rong Wang, Chunhui Zhao, Yangming Xu, Yinghui Liu, Wu Song, Xin Su & Bingmei Wang

  2. Jilin Provincial People’s Hospital, Changchun, 130021, China

    Yinghui Liu

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  1. Tao Jiang
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  2. Dai Yuan
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  3. Rong Wang
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  8. Xin Su
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Contributions

Material preparation, data collection and analysis were performed by TJ, DY, RW and CZ; the first draft of the manuscript was written by TJ; BW, YX and YL revised the manuscript; XS and WS conceived and designed the experiments. All authors read and approved the final manuscript.

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Correspondence to Wu Song, Xin Su or Bingmei Wang.

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The animal experiments and surgical procedures were approved by the Experimental Animal Ethics Committee of Changchun University of Chinese Medicine, in accordance with guidelines.

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Jiang, T., Yuan, D., Wang, R. et al. Echinacoside, a promising sortase A inhibitor, combined with vancomycin against murine models of MRSA-induced pneumonia. Med Microbiol Immunol 212, 421–435 (2023). https://doi.org/10.1007/s00430-023-00782-9

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