Elevated expression of GlpT and UhpT via FNR activation contributes to increased susceptibility to fosfomycin in Escherichia coli under anaerobic conditions.
Antimicrob Agents Chemother. 2015 Jul 27;
Authors: Kurabayashi K, Tanimoto K, Fueki S, Tomita H, Hirakawa H
A shortage of new antimicrobial agents is a critical issue at present, and together with the spread of MDR pathogens, use of fosfomycin to treat infections is being revisited as a "last resort option". This drug offers a particular benefit in that it is more effective against bacteria growing under oxygen-limited conditions unlike other commonly used antimicrobials such as fluoroquinolones and aminoglycosides. In this study, we showed that Escherichia coli species including the EHEC when anaerobically grown was more susceptible to fosfomycin than when aerobically grown, and investigated how its activity is enhanced during anaerobic growth in E. coli. Our quantitative PCR analysis and transport assay showed that E. coli cells grown under anaerobic conditions had a higher expression of glpT and uhpT encoding proteins that transport fosfomycin into the cells with their native substrates glycerol-3-phosphate and glucose-6-phosphate, and led to increased intracellular accumulation of the drug. Elevation of these genes expression during anaerobic growth requires FNR, the global transcriptional regulator that is activated under anaerobic conditions. Purified FNR bound to DNA fragments from glpT and uhpT regions upstream, suggesting it is an activator to elevate the expression of glpT and uhpT during anaerobic growth. We here conclude that increased antibacterial activity of fosfomycin to E. coli under anaerobic conditions is attributed to elevated expression of GlpT and UhpT following activation of FNR, then lead to increased uptake of the drug.
PMID: 26248376 [PubMed - as supplied by publisher]