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.