Abstract
To investigate the prevalence, location and genetic environments of fosfomycin-resistance (fos) genes in methicillin-resistant Staphylococcus aureus (MRSA) clinical strains, 67 fosfomycin-resistant MRSA strains were isolated from the blood and cerebrospinal fluid samples at a teaching hospital in Shanghai. The presence of fos genes in these clinical strains was detected by PCR and sequencing. The locations of fos genes were determined by Southern blotting and genetic environments were analyzed by primer walking sequencing. Multiple locus sequence typing (MLST) was used to characterize genetic diversity. Conjugation was performed to evaluate the transferability of fos genes. Among 67 fosfomycin-resistant MRSA strains, nine high level fosfomycin resistant strains (≥128 μg/ml) were fosB-positive. Three new subtypes of fosB, designated as fosB4, fosB5, and fosB6, were identified. fosB1, fosB4 or fosB6 genes were located on small plasmids (ca. 2.5 kb) and flanked by an analogous replication gene (rep). Differently, the fosB5 gene was surrounded by a shorter rep gene and two copies of a transposon gene (tnp) that shared high identity with the IS257-like transposon. Four MLST types were found among the nine fosB-positive strains. Transconjugants with the fosB genes were resistant to fosfomycin with MIC 64 or 128 μg/ml. In conclusion, different subtypes and genetic environment of fosB genes indicate that gene heterogeneity for fosfomycin resistance in MRSA isolates.
Highlights
Fosfomycin is a bactericidal antibiotic that was first discovered in 1969
The MIC of fosfomycin for the 67 methicillin-resistant Staphylococcus aureus (MRSA) strains ranged from 64 μg/ml to >256 μg/ml
The fosB genes found in S. aureus SA0406, SA1280 and SA1278 were different in nucleotide identity and deduced amino acid sequence from fosB1 genes discovered in plasmids from Staphylococcus spp. [17,18], chromosomal-derived fosB2 genes found in Bacillus anthracis [9] and the fosB3 gene from E. faecium [3] (Table 2 and Fig 1)
Summary
Fosfomycin is a bactericidal antibiotic that was first discovered in 1969. By irreversibly interfering with the first committed step of peptidoglycan biosynthesis, fosfomycin can hinder the cell wall synthesis in both Gram-positive and Gram-negative bacteria [1]. Due to its unique mechanism, fosfomycin alone or in combination with other antibiotics is used for the treatment of nosocomial infections due to multidrug-resistant (MDR) Gram-positive and Gram-negative bacteria. Among all plasmid-mediated resistance genes, only the fosB gene has been detected in Gram-positive pathogens [1]. The plasmids harboring fosB1 sized from 2.4 kb to 4.1 kb that confer resistance to fosfomycin have been found in Staphylococcus spp. The goal of this study is to characterize fosB gene among 67 fosfomycin-resistant MRSA clinical isolates
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