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Staphylococcus aureus COL: An Atypical Model Strain of MRSA That Exhibits Slow Growth and Antibiotic Tolerance due to
Claire E Stevens1, Ashley T Deventer1, Paul R Johnston2
1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews, UK.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) has been a pathogen of global concern since its emergence in the 1960s. As one of the first MRSA strains isolated, COL has become a common model strain of S. aureus. Here we report that COL is, in fact, an atypical strain of MRSA that exhibits slow growth and multidrug tolerance. Genomic analysis identified three mutated genes in COL (rpoB, gltX and prs) with links to tolerance. Allele swapping experiments between COL and the closely-related, nontolerant Newman strain uncovered a complex interplay between these genes. However, Prs (phosphoribosyl pyrophosphate [PRPP] synthetase) accounted for most of the growth and tolerance phenotype of COL. Biochemical and transcriptomic analysis revealed that COL does not exhibit slow growth as a result of partial stringent response activation, as previously proposed. Instead, the COL Prs mutation greatly reduces the PRPP synthetase activity of the enzyme and leads to downregulation of pyrimidine, histidine, and tryptophan synthesis, three pathways that rely on PRPP. Overall, our findings indicate that COL is an atypical, antibiotic-tolerant strain of MRSA whose isolation predates the previous first report of tolerance among clinical isolates. Characterization of clinical Prs mutations and their relationship with tolerance requires further investigation.
Insights
Methicillin-resistant Staphylococcus aureus (MRSA) strain COL exhibits atypical slow growth and multidrug tolerance due to a mutation in its phosphoribosyl pyrophosphate synthetase (Prs) enzyme. This finding challenges previous models and highlights Prs as a key factor in MRSA tolerance.
Area of Science:
- Microbiology
- Genomics
- Molecular Biology
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) is a significant global pathogen.
- The COL strain is a widely used MRSA model, but its characteristics are not fully understood.
- Previous studies suggested COL's slow growth was linked to stringent response activation.
Purpose of the Study:
- To investigate the genetic basis of slow growth and multidrug tolerance in the MRSA COL strain.
- To re-evaluate the proposed mechanism for COL's slow growth.
- To identify key genes contributing to MRSA antibiotic tolerance.
Main Methods:
- Genomic analysis to identify mutations in COL.
- Allele swapping experiments between COL and the Newman strain.
- Biochemical assays and transcriptomic analysis to study gene function and pathway regulation.
Main Results:
- COL harbors mutations in rpoB, gltX, and prs genes.
- A mutation in Prs (phosphoribosyl pyrophosphate synthetase) significantly contributes to COL's slow growth and tolerance.
- The Prs mutation reduces enzyme activity, downregulating pyrimidine, histidine, and tryptophan synthesis.
- COL's slow growth is not due to stringent response activation.
Conclusions:
- COL is an atypical MRSA strain with unique tolerance mechanisms predating other reported tolerant isolates.
- The Prs mutation is a primary driver of COL's slow growth and multidrug tolerance.
- Further research is needed to explore the role of clinical Prs mutations in MRSA tolerance.
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