Fosfomycin resistance protein A (FosA)

Fosfomycin resistance protein A (FosA) is a dimeric, metal-dependent glutathione S-transferase that serves as a major mechanism of resistance against the antibiotic fosfomycin in Gram-negative bacteria. It functions by catalyzing the nucleophilic attack of glutathione on the epoxide ring of fosfomycin, leading to the formation of an inactive glutathione-conjugate. This enzymatic inactivation prevents fosfomycin from inhibiting its primary target, MurA, thereby allowing bacterial cell wall synthesis to continue. FosA is found both on bacterial chromosomes (e.g., in Pseudomonas aeruginosa and Klebsiella pneumoniae) and on mobile genetic elements like plasmids (e.g., fosA3 in Escherichia coli), facilitating its rapid spread. The enzyme requires divalent manganese (Mn2+) and monovalent potassium (K+) ions for optimal catalytic activity. Because it significantly limits the clinical utility of fosfomycin, FosA is considered a high-priority target for the development of adjuvant therapies, such as FosA inhibitors like phosphonoformate, which could restore antibiotic susceptibility. The presence of FosA in clinical isolates is often associated with multidrug-resistant phenotypes, particularly in Enterobacteriaceae.

Other names

Fosfomycin-modifying enzymeGlutathione S-transferase FosAMn2+/K+-dependent glutathione S-transferase

Inhibition of FosA enzymatic activity to restore fosfomycin susceptibility