Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO

Yunfu Lu, Feifei Chen, Qingmin Zhao, Qiao Cao, Rongrong Chen, Huiwen Pan, Yanhui Wang, Haixin Huang, Ruimin Huang, Qian Liu, Min Li, Taeok Bae, Haihua Liang () and Lefu Lan ()
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Yunfu Lu: University of Chinese Academy of Sciences
Feifei Chen: University of Chinese Academy of Sciences
Qingmin Zhao: University of Chinese Academy of Sciences
Qiao Cao: University of Chinese Academy of Sciences
Rongrong Chen: University of Chinese Academy of Sciences
Huiwen Pan: University of Chinese Academy of Sciences
Yanhui Wang: University of Chinese Academy of Sciences
Haixin Huang: Chinese Academy of Sciences
Ruimin Huang: Chinese Academy of Sciences
Qian Liu: School of Medicine, Renji Hospital, Shanghai Jiao Tong University
Min Li: School of Medicine, Renji Hospital, Shanghai Jiao Tong University
Taeok Bae: Indiana University School of Medicine-Northwest
Haihua Liang: Northwest University
Lefu Lan: University of Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are key virulence determinants for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), an important human pathogen that causes a wide range of diseases. Here, using chemical and genetic approaches, we show that inhibition of TarO, the first enzyme in the wall teichoic acid (WTA) biosynthetic pathway, decreases the expression of genes encoding PSMs and SpA in the prototypical CA-MRSA strain USA300 LAC. Mechanistically, these effects are linked to the activation of VraRS two-component system that directly represses the expression of accessory gene regulator (agr) locus and spa. The activation of VraRS was due in part to the loss of the functional integrity of penicillin-binding protein 2 (PBP2) in a PBP2a-dependent manner. TarO inhibition can also activate VraRS in a manner independent of PBP2a. We provide multiple lines of evidence that accumulation of lipid-linked peptidoglycan precursors is a trigger for the activation of VraRS. In sum, our results reveal that WTA biosynthesis plays an important role in the regulation of virulence gene expression in CA-MRSA, underlining TarO as an attractive target for anti-virulence therapy. Our data also suggest that acquisition of PBP2a-encoding mecA gene can impart an additional regulatory layer for the modulation of key signaling pathways in S. aureus.

Date: 2023
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DOI: 10.1038/s41467-023-37310-5

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