Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239
<p>Staphylococcus aureus infections pose a serious challenge in healthcare due to the emergence of resistance to multiple antibiotics. ST239 is a multidrug-resistant MRSA strain that has been responsible for epidemics in healthcare settings across the globe since the late 1970s. However, in re...
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| Format: | Thesis |
| Language: | English |
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2019
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| _version_ | 1797050964790738944 |
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| author | Gill, J |
| author2 | MacLean, C |
| author_facet | MacLean, C Gill, J |
| author_sort | Gill, J |
| collection | OXFORD |
| description | <p>Staphylococcus aureus infections pose a serious challenge in healthcare due to the emergence of resistance to multiple antibiotics. ST239 is a multidrug-resistant MRSA strain that has been responsible for epidemics in healthcare settings across the globe since the late 1970s. However, in recent years there have been reports of strains that have successfully replaced ST239 as the dominant strain in clinical environments.</p>
<p>In 2004, Robinson and Enright hypothesised that ST239 is a natural hybrid that formed through a single large chromosomal replacement event between two distantly-related S. aureus strains, where 20% of the ancestral ST8-like genome was replaced with the homologous region from an ST30-like ancestor. In this thesis, I use a diverse range of ST239, ST8 and ST30 sequences from publicly-available sequencing repositories to make genomic comparisons between ST239 and its hypothesised ancestors. I confirm that the evolution of ST239 is consistent with the Robinson-Enright model, and investigate how the acquired and backbone regions of ST239 have adapted to evolutionary pressures in the same genome. There is evidence of weaker selective constraints on the acquired region of ST239 compared to the genomic backbone, as well as evidence of parallel evolution in antimicrobial resistance and virulence related genes, which suggests that antibiotics and the host immune response are important evolutionary pressures faced by ST239. This is consistent with the close relationship between ST239 and the SCCmec-III element, which encodes multiple antimicrobial resistance genes. In over 40,000 S. aureus sequences, SCCmec-III is strongly linked to ST239, with only a few rare exceptions. In contrast with previous estimates, the most recent common ancestor of the ST239 sequences is dated several years prior to the clinical introduction of methicillin, which suggests that use of earlier antimicrobials is more likely to have driven the global emergence of ST239.</p>
<p>Finally, I develop a method to calculate the relative competitive ability of a collection of 15 S. aureus isolates in co-culture, including ST239, ST8 and ST30 isolates, through whole-genome sequencing. Competitive ability and growth rate are not correlated, suggesting that these two fitness measures are independent. The ST239 isolates have greater antimicrobial resistance and overall lower fitness, however, fitness and antimicrobial resistance are not correlated. This may indicate that, although ST239 has been a globally successful multidrug-resistant epidemic MRSA strain, the extreme genetic transfer events in its early evolution have had an overall negative impact on fitness, contributing to its eventual decline.</p> |
| first_indexed | 2024-03-06T18:13:01Z |
| format | Thesis |
| id | oxford-uuid:03a88ebf-52c7-4697-b39b-e2594ccc7c11 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:13:01Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:03a88ebf-52c7-4697-b39b-e2594ccc7c112022-03-26T08:47:32ZEvolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239Thesishttp://purl.org/coar/resource_type/c_db06uuid:03a88ebf-52c7-4697-b39b-e2594ccc7c11Evolution (Biology)BioinformaticsMicrobiologyEnglishHyrax Deposit2019Gill, JMacLean, CWilson, D<p>Staphylococcus aureus infections pose a serious challenge in healthcare due to the emergence of resistance to multiple antibiotics. ST239 is a multidrug-resistant MRSA strain that has been responsible for epidemics in healthcare settings across the globe since the late 1970s. However, in recent years there have been reports of strains that have successfully replaced ST239 as the dominant strain in clinical environments.</p> <p>In 2004, Robinson and Enright hypothesised that ST239 is a natural hybrid that formed through a single large chromosomal replacement event between two distantly-related S. aureus strains, where 20% of the ancestral ST8-like genome was replaced with the homologous region from an ST30-like ancestor. In this thesis, I use a diverse range of ST239, ST8 and ST30 sequences from publicly-available sequencing repositories to make genomic comparisons between ST239 and its hypothesised ancestors. I confirm that the evolution of ST239 is consistent with the Robinson-Enright model, and investigate how the acquired and backbone regions of ST239 have adapted to evolutionary pressures in the same genome. There is evidence of weaker selective constraints on the acquired region of ST239 compared to the genomic backbone, as well as evidence of parallel evolution in antimicrobial resistance and virulence related genes, which suggests that antibiotics and the host immune response are important evolutionary pressures faced by ST239. This is consistent with the close relationship between ST239 and the SCCmec-III element, which encodes multiple antimicrobial resistance genes. In over 40,000 S. aureus sequences, SCCmec-III is strongly linked to ST239, with only a few rare exceptions. In contrast with previous estimates, the most recent common ancestor of the ST239 sequences is dated several years prior to the clinical introduction of methicillin, which suggests that use of earlier antimicrobials is more likely to have driven the global emergence of ST239.</p> <p>Finally, I develop a method to calculate the relative competitive ability of a collection of 15 S. aureus isolates in co-culture, including ST239, ST8 and ST30 isolates, through whole-genome sequencing. Competitive ability and growth rate are not correlated, suggesting that these two fitness measures are independent. The ST239 isolates have greater antimicrobial resistance and overall lower fitness, however, fitness and antimicrobial resistance are not correlated. This may indicate that, although ST239 has been a globally successful multidrug-resistant epidemic MRSA strain, the extreme genetic transfer events in its early evolution have had an overall negative impact on fitness, contributing to its eventual decline.</p> |
| spellingShingle | Evolution (Biology) Bioinformatics Microbiology Gill, J Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239 |
| title | Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239 |
| title_full | Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239 |
| title_fullStr | Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239 |
| title_full_unstemmed | Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239 |
| title_short | Evolutionary drivers of the rise and fall of a dominant hybrid MRSA, ST239 |
| title_sort | evolutionary drivers of the rise and fall of a dominant hybrid mrsa st239 |
| topic | Evolution (Biology) Bioinformatics Microbiology |
| work_keys_str_mv | AT gillj evolutionarydriversoftheriseandfallofadominanthybridmrsast239 |