Dataset Information

Comparative Analysis of Virulence and Toxin Expression of Vancomycin-Intermediate and Vancomycin-Sensitive Staphylococcus aureus Strains.

ABSTRACT: Previous studies on vancomycin-intermediate Staphylococcus aureus (VISA) have mainly focused on drug resistance, the evolution of differences in virulence between VISA and vancomycin-sensitive S. aureus (VSSA) requires further investigation. To address this issue, in this study, we compared the virulence and toxin profiles of pair groups of VISA and VSSA strains, including a series of vancomycin-resistant induced S. aureus strains-SA0534, SA0534-V8, and SA0534-V16. We established a mouse skin infection model to evaluate the invasive capacity of VISA strains, and found that although mice infected with VISA had smaller-sized abscesses than those infected with VSSA, the abscesses persisted for a longer period (up to 9 days). Infection with VISA strains was associated with a lower mortality rate in Galleria mellonella larvae compared to infection with VSSA strains (? 40% vs. ? 3% survival at 28 h). Additionally, VISA were more effective in colonizing the nasal passage of mice than VSSA, and in vitro experiments showed that while VISA strains were less virulent they showed enhanced intracellular survival compared to VSSA strains. RNA sequencing of VISA strains revealed significant differences in the expression levels of the agr, hla, cap, spa, clfB, and sbi genes and suggested that platelet activation is only weakly induced by VISA. Collectively, our findings indicate that VISA is less virulent than VSSA but has a greater capacity to colonize human hosts and evade destruction by the host innate immune system, resulting in persistent and chronic S. aureus infection.

SUBMITTER: Jin Y

PROVIDER: S-EPMC7661696 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Comparative Analysis of Virulence and Toxin Expression of Vancomycin-Intermediate and Vancomycin-Sensitive Staphylococcus aureus Strains.

Jin Ye Y Yu Xiao X Zhang Shuntian S Kong Xiaoyang X Chen Weiwei W Luo Qixia Q Zheng Beiwen B Xiao Yonghong Y

Frontiers in microbiology 20201030

Previous studies on vancomycin-intermediate Staphylococcus aureus (VISA) have mainly focused on drug resistance, the evolution of differences in virulence between VISA and vancomycin-sensitive S. aureus (VSSA) requires further investigation. To address this issue, in this study, we compared the virulence and toxin profiles of pair groups of VISA and VSSA strains, including a series of vancomycin-resistant induced S. aureus strains-SA0534, SA0534-V8, and SA0534-V16. We established a ...[more]

PMID: 33193280

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Project description:Resistance to antibiotics is an increasing problem and necessitates novel antibacterial therapies. The polyketide antibiotics cervimycin A to D are natural products of Streptomyces tendae HKI 0179 with promising activity against multidrug-resistant staphylococci and vancomycin-resistant enterococci. To initiate mode of action studies, we selected cervimycin C- and D-resistant (CmR) Staphylococcus aureus strains. Genome sequencing of CmR mutants revealed amino acid exchanges in the essential histidine kinase WalK, the Clp protease proteolytic subunit ClpP or the Clp ATPase ClpC, and the heat shock protein DnaK. Interestingly, all characterized CmR mutants harbored a combination of mutations in walK and clpP or clpC. In vitro and in vivo analyses showed that the mutations in the Clp proteins abolished ClpP or ClpC activity, and the deletion of clpP rendered S. aureus but not all Bacillus subtilis strains cervimycin-resistant. The essential gene walK was the second mutational hotspot in the CmR S. aureus strains, which decreased WalK activity in vitro and generated a vancomycin-intermediate resistant phenotype, with a thickened cell wall, a lower growth rate, and reduced cell lysis. Transcriptomic and proteomic analyses revealed massive alterations in the CmR strains compared to the parent strain S. aureus SG511, with major shifts in the heat shock regulon, the metal ion homeostasis, and the carbohydrate metabolism. Taken together, mutations in the heat shock genes clpP, clpC, and dnaK, and the walK kinase gene in CmR mutants induced a vancomycin-intermediate resistant phenotype in S. aureus, suggesting cell wall metabolism or the Clp protease system as primary target of cervimycin. IMPORTANCE Staphylococcus aureus is a frequent cause of infections in both the community and hospital setting. Resistance development of S. aureus to various antibiotics is a severe problem for the treatment of this pathogen worldwide. New powerful antimicrobial agents against Gram-positives are needed, since antibiotics like vancomycin fail to cure vancomycin-intermediate resistant S. aureus (VISA) and vancomycin-resistant enterococci (VRE) infections. One candidate substance with promising activity against these organisms is cervimycin, which is an antibiotic complex with a yet unknown mode of action. In our study, we provide first insights into the mode of action of cervimycins. By characterizing cervimycin-resistant S. aureus strains, we revealed the Clp system and the essential kinase WalK as mutational hotspots for cervimycin resistance in S. aureus. It further emerged that cervimycin-resistant S. aureus strains show a VISA phenotype, indicating a role of cervimycin in perturbing the bacterial cell envelope.

Project description:IntroductionVancomycin-intermediate Staphylococcus aureus (VISA) is typically associated with a decline in virulence. We previously reported a WalK(S221P) mutation that plays an important role in mediating vancomycin resistance in VISA XN108. Whether this mutation is implicated in bacterial virulence remains unknown.ObjectivesThis study aimed to investigate the effect of WalK(S221P) mutation on the virulence of VISA and the underlying mechanism of this effect.MethodsThe influence of WalK(S221P) mutation on VISA virulence and its underlying mechanism were explored using animal models, RNA-seq analysis, RT-qPCR, hemolytic assay, slide coagulase test, Western blot, β-galactosidase assay, and electrophoresis mobility shift assay (EMSA).ResultsCompared with XN108, WalK(S221P)-reverted strain XN108-R exacerbated cutaneous infections with increased lesion size and extensive inflammatory infiltration in mouse models. The bacterial loads of S. aureus XN108-R in murine kidney increased compared with those of XN108. RNA-seq analysis showed upregulation of a set of virulence genes in XN108-R, which exhibited greater hemolytic and stronger coagulase activities compared with XN108. Introduction of WalK(S221P) to methicillin-resistant S. aureus USA300 and methicillin-susceptible strain Newman increased the vancomycin resistance of the mutants, which exhibited reduced hemolytic activities and decreased expression levels of many virulence factors compared with their progenitors. WalK(S221P) mutation weakened agr promoter-controlled β-galactosidase activity. EMSA results showed that WalK-phosphorylated WalR could directly bind to the agr promoter region, whereas WalK(S221P)-activated WalR reduced binding to the target promoter. Inactivation of agr in S. aureus did not affect their vancomycin susceptibility but mitigated the virulence alterations caused by WalK(S221P) mutation.ConclusionThe results of our study indicate that WalK(S221P) mutation can enhance vancomycin resistance in S. aureus of diverse genetic backgrounds. WalK(S221P)- bearing S. aureus strains exhibit reduced virulence. WalK(S221P) mutation may directly impair the activation of the agr system by WalR, thereby decreasing the expression of virulence factors in VISA.

Dataset Information

Comparative Analysis of Virulence and Toxin Expression of Vancomycin-Intermediate and Vancomycin-Sensitive Staphylococcus aureus Strains.

Publications

Comparative Analysis of Virulence and Toxin Expression of Vancomycin-Intermediate and Vancomycin-Sensitive <i>Staphylococcus aureus</i> Strains.

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