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

Lu，Yunfu1,2,3; Chen，Feifei1,2,4; Zhao，Qingmin1,2,3; Cao，Qiao1,2,4; Chen，Rongrong1,2,3; Pan，Huiwen1,2,3; Wang，Yanhui1,2,3; Huang，Haixin2; Huang，Ruimin2,3; Liu，Qian5; Li，Min5; Bae，Taeok6; Liang，Haihua4,7; Lan，Lefu1,2,3,4

2023-12-01

10.1038/s41467-023-37310-5

Nature Communications   影响因子和分区

2041-1723

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.

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Science and Technology Commission of Shanghai Municipality[19JC1416400];National Natural Science Foundation of China-Yunnan Joint Fund[31870127];National Natural Science Foundation of China-Yunnan Joint Fund[32270184];State Key Laboratory of Drug Research[SIMM2003ZZ-03];State Key Laboratory of Drug Research[SIMM2205KF-07];

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001063479500020

NATURE PORTFOLIO

2-s2.0-85150763811

Scopus

1.School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,310024,China
2.State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China
3.University of Chinese Academy of Sciences,Beijing,No. 19A Yuquan Road,100049,China
4.College of Life Science,Northwest University,Xi’an,710127,China
5.Department of Laboratory Medicine,School of Medicine,Renji Hospital,Shanghai Jiao Tong University,Shanghai,200127,China
6.Department of Microbiology and Immunology,Indiana University School of Medicine-Northwest,Gary,46408,United States
7.School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China

Lu，Yunfu,Chen，Feifei,Zhao，Qingmin,et al. Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO[J]. Nature Communications,2023,14(1).

Lu，Yunfu.,Chen，Feifei.,Zhao，Qingmin.,Cao，Qiao.,Chen，Rongrong.,...&Lan，Lefu.(2023).Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO.Nature Communications,14(1).

Lu，Yunfu,et al."Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO".Nature Communications 14.1(2023).