Abstract
BackgroundFosfomycin is an antibiotic that has seen a revival in use due to its unique mechanism of action and efficacy against isolates resistant to many other antibiotics. In Escherichia coli, fosfomycin often selects for loss-of-function mutations within the genes encoding the sugar importers, GlpT and UhpT. There has, however, not been a genome-wide analysis of the basis for fosfomycin susceptibility reported to date.MethodsHere we used TraDIS-Xpress, a high-density transposon mutagenesis approach, to assay the role of all genes in E. coli involved in fosfomycin susceptibility.ResultsThe data confirmed known fosfomycin susceptibility mechanisms and identified new ones. The assay was able to identify domains within proteins of importance and revealed essential genes with roles in fosfomycin susceptibility based on expression changes. Novel mechanisms of fosfomycin susceptibility that were identified included those involved in glucose metabolism and phosphonate catabolism (phnC-M), and the phosphate importer, PstSACB. The impact of these genes on fosfomycin susceptibility was validated by measuring the susceptibility of defined inactivation mutants.ConclusionsThis work reveals a wider set of genes that contribute to fosfomycin susceptibility, including core sugar metabolism genes and two systems involved in phosphate uptake and metabolism previously unrecognized as having a role in fosfomycin susceptibility.
Highlights
The increasing prevalence of bacteria which are resistant to clinically important antibiotics has led to searches for alternative options to treat problematic infections [1]
Fosfomycin has a unique mode of action where it targets the initial stages of peptidoglycan biosynthesis by acting as a phosphoenolypyruvate analogue and inhibiting MurA [3]
This means that fosfomycin retains activity against strains producing beta-lactamases as it targets an earlier stage in peptidoglycan biosynthesis
Summary
The increasing prevalence of bacteria which are resistant to clinically important antibiotics has led to searches for alternative options to treat problematic infections [1]. Fosfomycin has a unique mode of action where it targets the initial stages of peptidoglycan biosynthesis by acting as a phosphoenolypyruvate analogue and inhibiting MurA [3]. This means that fosfomycin retains activity against strains producing beta-lactamases as it targets an earlier stage in peptidoglycan biosynthesis. This is attractive given the high prevalence of production of beta-lactamase enzymes of many families in important pathogens. In Enterobacteriaceae, fosfomycin enters the cell by acting as a mimic for two nutrient importer systems; GlpT and UhpT [4]
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