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Open Access Research article

Revealing fosfomycin primary effect on Staphylococcus aureus transcriptome: modulation of cell envelope biosynthesis and phosphoenolpyruvate induced starvation

Marko Petek1*, Špela Baebler1, Drago Kuzman2, Ana Rotter1, Zdravko Podlesek3, Kristina Gruden1, Maja Ravnikar1 and Uroš Urleb2

Author Affiliations

1 Department of Biotechnology and Systems Biology, National Institute of Biology, Večna pot 111, Ljubljana, SI-1000, Slovenia

2 Novartis BPO Mengeš, Lek Pharmaceuticals d.d., Kolodvorska 27, Mengeš, SI-1234, Slovenia

3 Department of Biology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, Ljubljana, SI-1000, Slovenia

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BMC Microbiology 2010, 10:159  doi:10.1186/1471-2180-10-159

Published: 1 June 2010

Abstract

Background

Staphylococcus aureus is a highly adaptable human pathogen and there is a constant search for effective antibiotics. Fosfomycin is a potent irreversible inhibitor of MurA, an enolpyruvyl transferase that uses phosphoenolpyruvate as substrate. The goal of this study was to identify the pathways and processes primarily affected by fosfomycin at the genome-wide transcriptome level to aid development of new drugs.

Results

S. aureus ATCC 29213 cells were treated with sub-MIC concentrations of fosfomycin and harvested at 10, 20 and 40 minutes after treatment. S. aureus GeneChip statistical data analysis was complemented by gene set enrichment analysis. A visualization tool for mapping gene expression data into biological pathways was developed in order to identify the metabolic processes affected by fosfomycin. We have shown that the number of significantly differentially expressed genes in treated cultures increased with time and with increasing fosfomycin concentration. The target pathway - peptidoglycan biosynthesis - was upregulated following fosfomycin treatment. Modulation of transport processes, cofactor biosynthesis, energy metabolism and nucleic acid biosynthesis was also observed.

Conclusions

Several pathways and genes downregulated by fosfomycin have been identified, in contrast to previously described cell wall active antibiotics, and was explained by starvation response induced by phosphoenolpyruvate accumulation. Transcriptomic profiling, in combination with meta-analysis, has been shown to be a valuable tool in determining bacterial response to a specific antibiotic.