Abstract
Staphylococcus aureus strains that are susceptible to the β-lactam antibiotic oxacillin despite carrying mecA (OS-MRSA) cause serious clinical problems globally because of their ability to easily acquire β-lactam resistance. Understanding the genetic mechanism(s) of acquisition of the resistance is therefore crucial for infection control management. For this purpose, a whole-genome sequencing-based analysis was performed using 43 clinical OS-MRSA strains and 100 mutants with reduced susceptibility to oxacillin (MICs 1.0–256 µg/mL) generated from 26 representative OS-MRSA strains. Genome comparison between the mutants and their respective parent strains identified a total of 141 mutations in 46 genes and 8 intergenic regions. Among them, the mutations are frequently found in genes related to RNA polymerase (rpoBC), purine biosynthesis (guaA, prs, hprT), (p)ppGpp synthesis (relSau), glycolysis (pykA, fbaA, fruB), protein quality control (clpXP, ftsH), and tRNA synthase (lysS, gltX), whereas no mutations existed in mec and bla operons. Whole-genome transcriptional profile of the resistant mutants demonstrated that expression of genes associated with purine biosynthesis, protein quality control, and tRNA synthesis were significantly inhibited similar to the massive transcription downregulation seen in S. aureus during the stringent response, while the levels of mecA expression and PBP2a production were varied. We conclude that a combination effect of mecA upregulation and stringent-like response may play an important role in acquisition of β-lactam resistance in OS-MRSA.
Highlights
Staphylococcus aureus strains that are susceptible to the β-lactam antibiotic oxacillin despite carrying mecA (OS-Methicillin-resistant S. aureus (MRSA)) cause serious clinical problems globally because of their ability to acquire β-lactam resistance
Our results revealed that all strains maintained the typical characteristics of OS-MRSA, including mecA positivity and susceptibility to oxacillin, but they were susceptible to oxacillin with minimum inhibitory concentration (MIC) ranging from 0.125 to 2 μg/mL
Since its first description in 1991, OS-MRSA15,38, which is related to borderline methicillin-resistant MRSA39, has been frequently isolated in hospital and community settings with a prevalence rate of 0.62 – 33.7%12,15,18,20,40,41
Summary
Staphylococcus aureus strains that are susceptible to the β-lactam antibiotic oxacillin despite carrying mecA (OS-MRSA) cause serious clinical problems globally because of their ability to acquire β-lactam resistance. Understanding the genetic mechanism(s) of acquisition of the resistance is crucial for infection control management For this purpose, a whole-genome sequencingbased analysis was performed using 43 clinical OS-MRSA strains and 100 mutants with reduced susceptibility to oxacillin (MICs 1.0–256 μg/mL) generated from 26 representative OS-MRSA strains. Whole-genome transcriptional profile of the resistant mutants demonstrated that expression of genes associated with purine biosynthesis, protein quality control, and tRNA synthesis were significantly inhibited similar to the massive transcription downregulation seen in S. aureus during the stringent response, while the levels of mecA expression and PBP2a production were varied. A collection of 43 clinical OS-MRSA strains and 100 mutants with reduced susceptibility to β-lactam resistance selected by exposing the OS-MRSA to oxacillin were analyzed to identify genome mutations responsible for β-lactam resistance
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