Abstract
BackgroundThe ability of Staphylococcus aureus to invade tissues and cause an infectious disease is the result of a multi-factorial process supported by the huge number of virulence factors inherent to this microorganism tightly regulated by the accessory gene regulator (agr). During antimicrobial therapy bacteria may be exposed to sub-inhibitory concentrations (subMICs) of antibiotics that may trigger transcriptional changes that may have an impact on the pathogenesis of infection. The objective of this study was to investigate the effect of oxacillin sub-MICs on agr system expression as the key component in the regulation of virulence in methicillin-susceptible (MSSA) and -resistant S. aureus (MRSA) strains. Furthermore, we studied the genetic basis of the agr locus and their potential association with the expression levels.MethodsWe have examined the expression of RNAIII and agrA mRNA as biomarkers for agr expression in the presence and absence of oxacillin subMICs in 10 MSSA and 4 MRSA clinical strains belonging to 5 clonal complexes (CC45-agrI, CC8-agrI, CC5-agrII, CC15-agrII and CC30-agrIII) causing endovascular complications. The DNA sequences of agr locus were obtained by whole genome sequencing.ResultsOur results revealed that exposure to subMICs of oxacillin had an impact on agr locus expression modifying the relative levels of expression with increases in 11 strains and with decreases in 3 strains. Thereby, the exposure to subMICs of oxacillin resulted in higher levels of expression of agr in CC15 and CC45 and lower levels in CC30. We also observed the presence of mutations in agrC and agrA in 13/14 strains with similar mutation profiles among strains within individual CCs except for strains of CC5. Although, agr expression levels differed among strains within CCs, the presence of these mutations was associated with differences in agr expression levels in most cases.ConclusionsChanges in agr expression induced by exposure to oxacillin subMICs should be considered because they could lead to changes in the virulence modulation and have an adverse effect on the course of infection, especially in certain clonal complexes.
Highlights
The ability of Staphylococcus aureus to invade tissues and cause an infectious disease is the result of a multi-factorial process supported by the huge number of virulence factors inherent to this microorganism tightly regulated by the accessory gene regulator
Expression of agr locus in the presence of oxacillin Sub-inhibitory concentrations (subMICs) in stationary phase and its relationship with the Clonal complexes (CC), agr type and methicillin resistance The exposure to subMICs of oxacillin in stationary phase resulted in a trend to higher RNAIII transcript levels than in absence of the antimicrobial agent for 11/14 strains being statistically significant for 5 strains of them (p < 0.05) (Fig. 1)
In order to investigate the association between agr locus expression and methicillin resistance profile we studied the agr locus expression in the strains classified as methicillinsusceptible S. aureus (MSSA) and methicillin resistant S. aureus (MRSA) and we found higher agrA and RNAIII levels of gene expression for both groups in the presence of subMICs of oxacillin than in absence of this antibiotic, this trend was not statistically significant (Table 3)
Summary
The ability of Staphylococcus aureus to invade tissues and cause an infectious disease is the result of a multi-factorial process supported by the huge number of virulence factors inherent to this microorganism tightly regulated by the accessory gene regulator (agr). Under conditions of high cell density, agr is responsible for the increased expression of many toxins and degradative exoenzymes, and decreased expression of several colonization factors. This regulation is important for the timing of virulence factor expression during infection [5]. Thereby, when adhesion to host tissue is crucial, cell density and agr expression are low, resulting in an increase in the surface virulence factors that are required for the colonization process. The increased cell density results in higher agr expression that leads to production of toxins which trigger the host inflammatory response [6, 7]. The agr system up-regulates the production of secreted virulence factors such as exotoxins, and downregulates the production of cell associated virulence factors [5, 8,9,10]
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