Abstract
The development of vancomycin (VCM) resistance in Staphylococcus aureus threatens global health. Studies of the VCM-resistance mechanism and alternative therapeutic strategies are urgently needed. We mutagenized S. aureus laboratory strains and methicillin-resistant S. aureus (MRSA) with ethyl methanesulfonate, and isolated mutants that exhibited high resistance to VCM (minimum inhibitory concentration = 32 μg/ml). These VCM-resistant strains were sensitive to linezolid and rifampicin, and partly to arbekacin and daptomycin. Beta-lactams had synergistic effects with VCM against these mutants. VCM-resistant strains exhibited a 2-fold increase in the cell wall thickness. Several genes were commonly mutated among the highly VCM-resistant mutants. These findings suggest that MRSA has a potential to develop high VCM resistance with cell wall thickening by the accumulation of mutations.
Highlights
The development of vancomycin (VCM) resistance in Staphylococcus aureus threatens global health
VCM-resistant S. aureus strains by serial mutagenesis using RN4220, a methicillin-sensitive laboratory strain
To the best of our knowledge, this is the first report of an experimental development of highly VCM-resistant S. aureus mutants from several different origins followed by their genomic comparisons
Summary
The development of vancomycin (VCM) resistance in Staphylococcus aureus threatens global health. We mutagenized S. aureus laboratory strains and methicillin-resistant S. aureus (MRSA) with ethyl methanesulfonate, and isolated mutants that exhibited high resistance to VCM (minimum inhibitory concentration = 32 μg/ml). There was an early report of VRSA with high VCM MIC developed in a laboratory[3], the phenotypic and genetic characteristics of the highly VCM-resistant strains were not fully elucidated. In the early 2000s, researchers reported that S. aureus strains acquiring the vanA gene by transposon and plasmid transfer from VCM-resistant Enterococcus showed an extremely high MIC to VCM4,5. We mutagenized S. aureus laboratory strains and clinical isolates to facilitate the development of resistance and selected highly VCM-resistant cells. We characterized the phenotypes, including the antibiotic susceptibility profiles, cell structure morphologies, and gene mutations of these VCM-resistant strains
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