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

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.

SUBMITTER: Lu Y

PROVIDER: S-EPMC10032271 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Lu Yunfu Y Chen Feifei F Zhao Qingmin Q Cao Qiao Q Chen Rongrong R Pan Huiwen H Wang Yanhui Y Huang Haixin H Huang Ruimin R Liu Qian Q Li Min M Bae Taeok T Liang Haihua H Lan Lefu L

Nature communications 20230322 1

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. Mecha ...[more]

PMID: 36949052

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Project description:Staphylococcus aureus (S. aureus) constantly evolves under host and environment pressures. The monitoring network is essential in assessing the epidemiology of S. aureus infections. A total of 555 S. aureus isolates were collected from five hospitals in three different geographical regions of China for the investigation of molecular characteristics, antibiotic resistance, virulence gene, and wall teichoic acid (WTA) glycosyltransferase gene profiles. 233 (42.0%) isolates were identified as MRSA, and 323 (58.2%) were defined as multidrug-resistant (MDR) isolates. MRSA prevalence showed no significant difference among the three regions. In contrast, the MDR prevalence was significantly higher in central China than that in northern China (63.5% vs. 50.8%, P < 0.05). Thirty-eight sequence types (STs) belonging to 17 clone complexes (CCs) and 126 distinct spa-types were identified. The most prevalent clone was ST59-t437 (9.7%, 54/555), followed by ST22-t309 (7.6%, 42/555) and ST5-t2460 (7.2%, 40/555). Most ST59-t437 and ST5-t2460 were MRSA isolates, whereas most ST22-t309 was MSSA isolates. The predominant clones varied in different geographical areas. The distribution of the pvl, etb, tsst, clfb, sdrC, sdrD, hlg, fnbA, and hla genes showed significant differences among different regions. We found five WTA glycosyltransferase gene profiles, with tarP-/tarS+/tarM-/tagN- being the most common combination. Remarkably, the tarP gene was identified in more CCs than just CC5 and CC398. All of 16 tarP-positive isolates also contained the tarS. Moreover, tarS was present in almost all S. aureus isolates except 10 ST630 isolates. The tagN gene was only detected in 10 of 12 ST630 S. aureus isolates without tarS. The tarM gene was absent in CC5 and CC398. In brief, there were regional differences among molecular characteristics, antibiotic resistance, and virulence gene profiles. The tarS-negative ST630 lineage carried the tagN, which was never found before, indicating that it may be capable of expressing GroP-α-GalNAc WTA and exchanging mobile genetic elements with coagulase-negative staphylococci (CoNS).

Project description:Multiple mechanisms have been correlated with daptomycin-resistance (DAP-R) in Staphylococcus aureus. However, one common phenotype observed in many DAP-R S. Aureus strains is a thickened cell wall (CW). The first evidence for an impact of CW-linked glycopolymers on this phenotype was recently demonstrated in a single, well-characterized DAP-R methicillin-susceptible S. aureus (MSSA) strain. In this isolate the thickened CW phenotype was linked to an increased production and D-alanylation of wall teichoic acids (WTA). In the current report, we extended these observations to methicillin-resistant daptomycin-sensitive/daptomyin-resistant (DAP-S/DAP-R) strain-pairs. These pairs included methicillin-resistant S. aureus (MRSA) isolates with and without single nucleotide polymorphisms (SNPs) in mprF (a genetic locus linked to DAP-R phenotype). We found increased CW dry mass in all DAP-R vs DAP-S isolates. This correlated with an increased expression of the WTA biosynthesis gene tagA, as well as an increased amount of WTA in the DAP-R vs DAP-S isolates. In addition, all DAP-R isolates showed a higher proportion of WTA D-alanylation vs their corresponding DAP-S isolate. We also detected an increased positive surface charge amongst the DAP-R strains (presumably related to the enhanced D-alanylation). In comparing the detailed CW composition of all isolate pairs, substantive differences were only detected in one DAP-S/DAP-R pair. The thickened CW phenotype, together with an increased surface charge most likely contributes to either: i) a charge-dependent repulsion of calcium complexed-DAP; and/or ii) steric-limited access of DAP to the bacterial cell envelope target. Taken together well-defined perturbations of CW structural and functional metrics contribute to the DAP-R phenotype and are common phenotypes in DAP-R S. Aureus isolates, both MSSA and MRSA. Note: Although "daptomycin-nonsusceptibility" is the generally accepted terminology, we have utilized the term "daptomycin resistance" for ease of presentation in this manuscript.

Dataset Information

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

Publications

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

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