The novel fosfomycin resistance gene fosY is present on a genomic island in CC1 methicillin-resistant Staphylococcus aureus

Abstract

Fosfomycin has gained attention as a combination therapy for methicillin-resistant Staphylococcus aureus infections. Hence, the detection of novel fosfomycin-resistance mechanisms in S. aureus is important. Here, the minimal inhibitory concentrations (MICs) of fosfomycin in CC1 methicillin-resistant S. aureus were determined. The pangenome analysis and comparative genomics were used to analyse CC1 MRSA. The gene function was confirmed by cloning the gene into pTXΔ. A phylogenetic tree was constructed to determine the clustering of the CC1 strains of S. aureus. We identified a novel gene, designated fosY , that confers fosfomycin resistance in S. aureus . The FosY protein is a putative bacillithiol transferase enzyme sharing 65.9–77.5% amino acid identity with FosB and FosD, respectively. The function of fosY in decreasing fosfomycin susceptibility was confirmed by cloning it into pTXΔ. The pTX- fosY transformant exhibited a 16-fold increase in fosfomycin MIC. The bioinformatic analysis showed that fosY is in a novel genomic island designated RI fosY (for “resistance island carrying fosY ”) that originated from other species. The global phylogenetic tree of ST1 MRSA displayed this fosY -positive ST1 clone, originating from different regions, in the same clade. The novel resistance gene in the fos family, fosY , and a genomic island, RI fosY , can promote cross-species gene transfer and confer resistance to CC1 MRSA causing the failure of clinical treatment. This emphasises the importance of genetic surveillance of resistance genes among MRSA isolates.

Molecular Basis of Non-β-Lactam Antibiotics Resistance in Staphylococcus aureus

“…The fosfomycin-inactivating enzyme thiol-S-transferase (encoded by fosB gene) [ 53 , 54 ] catalyzes the inactivation of fosfomycin antibiotic in S. aureus [ 53 , 54 ]. FosY protein, a putative bacillithiol transferase (encoded by fosY gene present on a genomic island) which shares 65.9–77.5% amino acid identity with FosB and FosD, respectively, confers resistance to fosfomycin in clonal complex 1 (CC1) MRSA isolate from China [ 217 ]. The chromosomally encoded major facilitator superfamily efflux transporter Tet38 (encoded by tet38 gene) of S. aureus acts as an efflux transporter of fosfomycin, which is affected by glycerol-3-phosphate (G3P) [ 216 ].…”