Mobile fosfomycin resistance genes in Enterobacteriaceae-An increasing threat

Antimicrobial resistance is one of the major threats to the health and welfare of both humans and animals. The shortage of new antimicrobial agents has led to the re-evaluation of old antibiotics such as fosfomycin as a potential regimen for treating multidrug-resistant bacteria especially extended-spectrum-beta-lactamase- and carbapenemase-producing Enterobacteriaceae. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits the initial step of the cell wall biosynthesis. Fosfomycin resistance can occur due to mutation in the drug uptake system or by the acquisition of fosfomycin-modifying enzymes. In this review, we focus on mobile fosfomycin-resistant genes encoding glutathione-S-transferase which are mainly responsible for fosfomycin resistance in Enterobacteriaceae, that is, fosA and its subtypes, fosC2, and the recently described fosL1-L2. We summarized the proposed origins of the different resistance determinants and highlighted the different plasmid types which are attributed to the dissemination of fosfomycin-modifying enzymes. Thereby, IncF and IncN plasmids play a predominant role. The detection of mobile fosfomycin-resistant genes in Enterobacteriaceae has increased in recent years. Similar to the situation in (East) Asia, the most frequently detected fosfomycin-resistant gene in Europe is fosA3. Mobile fosfomycin-resistant genes have been detected in isolates of human, animal, food, and environmental origin which leads to a growing concern regarding the risk of spread of such bacteria, especially Escherichia coli and Salmonella, at the human-animal-environment interface.