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Staphylococcus aureus walKR mutants (TPS3130 and TPS3190) vs. parent strains (JKD6009 and JKD6004)

ABSTRACT: WalKR is an essential two component regulatory system in S. aureus, thought to control cell wall metabolism. Using genome sequencing of 5 paired clinical isolates of vancomycin-susceptible and vancomycin-intermediate S. aureus we found frequent, but unique, mutations in this locus. To investigate the contribution of these mutations to vancomycin resistance allelic replacement WalK (G223D) and WalR (K208R) mutants were generated and compared to the parent strains. Mutations in walk and walR led to increased vancomycin resistance, reduced biofilms formation and attenuation of virulence, demonstrating that minor genetic changes in this locus can lead to significant changes in bacterial resistance and virulence. Microarray transcriptional comparisons were performed to investigate the regulatory effects of the WalK (G223D) and WalR (K208R) mutations, and demonstrated that while changes in genes affecting cell wall metabolism were detected, more dramatic changes were found in regulation of cellular metabolism.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE29157 | GEO | 2012/06/01

SECONDARY ACCESSION(S): PRJNA140011

REPOSITORIES: GEO

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Project description:The phenotype “intermediate vancomycin resistance” in Staphylococcus aureus (CLSI: MIC = 4-8 mg/L) has been assigned to changes that lead to alterations in cell wall synthesis and morphology. Most vancomycin intermediately resistant S. aureus (VISA) strains are characterised by an increased cell wall thickness as a consequence of an activated cell wall biosynthesis and decreased autolysis. The purpose of this study was to analyse the genetic basis of the vancomycin resistance mechanism of the clinical VISA isolate SA137/93A and its spontaneous mutant strain SA137/93G. The methicillin-resistant S. aureus (MRSA) SA137/93A was isolated from a tracheal secretion and displays heterogeneous intermediate vancomycin resistance (hVISA strain, MIC: 8 mg/L in BHI). Subculturing in presence of 6 mg/L vancomycin generated a mutant with homogeneous intermediate vancomycin resistance, that showed an MIC value of 16 mg/L in BHI and was designated SA137/93G. PFGE profiles and phage typing of the strains showed that they were members of the Iberian clone (ST247), which was prevalent in Germany in the early nineties under the designation “Northern German epidemic strain”. Both strains possess a thickened cell wall. However, the vancomycin resistance of strain SA137/93A is most probably enhanced by an increased amount of free D-Ala-D-Ala termini in the cell wall, which is due to decreased crosslinking, whereas the mutant strain SA137/93G shows normal crosslinking. Moreover, strain SA137/93A displays an increased expression of the essential two-component system yycFGHI as a consequence of an IS256 insertion in the promoter region, while strain SA137/93G is characterised by an insertion of IS256 into the gene tcaA. Although both insertions were shown to correlate with a decrease in susceptibility to vancomycin, the difference in the vancomycin resistance level of the strain pair could be mainly attributed to the disruption of tcaA in the mutant.This study was conducted to identify resistance mechanisms that both strains might have in common. To this end we compared the transcriptomes of both strains with that of the closely related vancomycin susceptible MRSA/VSSA strain SA1450/94 (MIC: 2 mg/L). We found that the genes of the capsule biosynthesis were the only genes with higher expression in both VISA strains. Keywords: strain comparison

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Staphylococcus aureus walKR mutants (TPS3130 and TPS3190) vs. parent strains (JKD6009 and JKD6004)

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