Diversity in fosfomycin resistance proteins

Certain strains of the soil microorganism Streptomyces produce an antibiotic, fosfomycin [(1 R,2 S)-epoxypropylphosphonic acid], which is effective against both Gram-positive and Gram-negative pathogens by inhibiting the first committed step in cell-wall biosynthesis. Fosfomycin resistance proteins are metallo-enzymes that are known to inactivate the antibiotic by the addition of nucleophiles such as water, glutathione (GSH), l-cysteine and bacillithiol (BSH) to the oxirane ring of the molecule. Progress in the characterisation of FosB-type fosfomycin resistance proteins found in many Gram-positive organisms has been slow. This paper provides a brief description of the diversity of fosfomycin resistance proteins in general and, more specifically, new data characterising the substrate selectivity, structure, mechanism and metal-ion dependence of FosB enzymes from pathogenic strains of Staphylococcus and Bacillus. These new findings include the high-resolution X-ray diffraction structures of FosB enzymes from Staphylococcus aureus and Bacillus cereus in various liganded states and kinetic data that suggest that Mn(II) and BSH are the preferred divalent cation and thiol substrate for the reaction, respectively. The discovery of the inhibition of the enzyme by Zn(II) led to the determination of a ternary structure of the FosB·Zn(II)·fosfomycin·l-Cys complex which reveals both substrates present in a pose prior to reaction.