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staphylococcus

Abstract

Background

To unravel molecular targets involved in glycopeptide resistance, three isogenic strains of Staphylococcus aureus with different susceptibility levels to vancomycin or teicoplanin were subjected to whole-genome microarray-based transcription and quantitative proteomic profiling. Quantitative proteomics performed on membrane extracts showed exquisite inter-experimental reproducibility permitting the identification and relative quantification of 30% of the predicted S. aureus proteome.

Results

In the absence of antibiotic selection pressure, comparison of stable resistant and susceptible strains revealed 94 differentially expressed genes and 178 proteins. As expected, only partial correlation was obtained between transcriptomic and proteomic results during stationary-phase. Application of massively parallel methods identified one third of the complete proteome, a majority of which was only predicted based on genome sequencing, but never identified to date. Several over-expressed genes represent previously reported targets, while series of genes and proteins possibly involved in the glycopeptide resistance mechanism were discovered here, including regulators, global regulator attenuator, hyper-mutability factor or hypothetical proteins. Gene expression of these markers was confirmed in a collection of genetically unrelated strains showing altered susceptibility to glycopeptides.

Conclusion

Our proteome and transcriptome analyses have been performed during stationary-phase of growth on isogenic strains showing susceptibility or intermediate level of resistance against glycopeptides. Altered susceptibility had emerged spontaneously after infection with a sensitive parental strain, thus not selected

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in vitro. This combined analysis allows the identification of hundreds of proteins considered, so far as hypothetical protein. In addition, this study provides not only a global picture of transcription and expression adaptations during a complex antibiotic resistance mechanism but also unravels potential drug targets or markers that are constitutively expressed by resistant strains regardless of their genetic background, amenable to be used as diagnostic targets.

The Gram-positive bacterium Staphylococcus aureus is an important human pathogen that has become increasingly resistant to a wide range of antibiotics over the last two decades. The emergence of multidrug-resistant isolates of methicillin-resistant S. aureus (MRSA) exhibiting also decreased susceptibilities to glycopeptides (glycopeptide-intermediate S. aureus, GISA) represents a crucial challenge for antimicrobial therapy, antimicrobial susceptibility testing, and hospital infection control. After initial description in Japan of MRSA strains with decreased susceptibility to glycopeptides [1], clinical isolates showing similar phenotypes were repeatedly reported in various countries [2-6]. These strains are distinct from high-level glycopeptide resistant isolates (VRSA) that result from the acquisition of the vanA gene from Enterococcus faecalis [7]. Their potential spreading appears of particular concern since glycopeptides represent the last barrier drugs effective against MRSA. In addition, intensive use of glycopeptides will probably contribute to the selection of other resistant strains, as already observed for numerous antimicrobial agents [8].

Vancomycin is a natural product, isolated from the bacteria Amycolatopsis orientalis in the early fifties [9]. Binding of this molecule to the N-acyl D-ala-D-ala residue of bacterial peptidoglycan through five strong hydrogen bonds inhibits cross-linking of the cell-wall [10]. Vancomycin acts therefore immediately upstream of the transpeptidase, the target of β-lactam antibiotics. Structure and mechanism of action of teicoplanin are similar to that of vancomycin

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