The stabilisation of genetic elements carrying antibiotic resistance genes - BfH, AfS, ENWW

Lead Research Organisation: University of Oxford
Department Name: Interdisciplinary Bioscience DTP

Abstract

Antibiotic resistant bacteria are one of the biggest public health threats of the 21st Century. Antibiotic resistance genes are often carried on mobile genetic elements (MGEs), which allow resistance genes to be transmitted horizontally, facilitating the spread of resistance between bacteria. This additional genetic material also carries a fitness cost, reducing the overall fitness of the bacterium. However, instead of being lost due to their unstable nature, antibiotic resistance genes have been observed to persist over extended periods of time, even in the absence of antibiotics. Many examples of the long-term incorporation of MGEs exist in nature, for example Staphylococcus aureus is able to carry many MGEs, including SCCmec which is responsible for the methicillin resistance phenotype in MRSA (methicillin-resistant S. aureus). This project will study the globally successful MRSA strain, ST239, which is a hybrid strain that was founded from two parental strains, ST8 and ST30. ST239 contains SCCmecIII, one of the largest bacterial MGEs, which confers resistance to methicillin as well as a large range of other antibiotics, antiseptics and heavy metals. Both experimental and bioinformatics approaches will be used to study the evolution and fitness of ST239, alongside that of its two parent strains ST8 and ST30, to investigate the stabilisation of the genetic elements carrying resistance genes which have enabled the hybrid strain ST239 to persist in the long term.

BBSRC priority areas
This research addresses the following BBSRC priority areas;
- Combatting antimicrobial resistance
- Data driven biology

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011224/1 01/10/2015 30/09/2023
1810142 Studentship BB/M011224/1 01/10/2015 31/12/2019 Jacqueline Louise Gill
 
Description 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.

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 my 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.

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.
Exploitation Route The outcomes of this funding will be written up in a scientific journal and published for use by others.
Sectors Healthcare

 
Description Gave evidence to the Health and Social Care Select Committee's Inquiry into Antimicrobal Resistance (AMR)
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
URL https://publications.parliament.uk/pa/cm201719/cmselect/cmhealth/962/962.pdf
 
Description Medical Research Foundation Antimicrobial Resitance Training Workshop Presentation to Policy Makers
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description RCUK Policy Internship at Parliamentary Office for Sceicne and Technology (POST)
Geographic Reach National 
Policy Influence Type Citation in other policy documents
URL http://researchbriefings.parliament.uk/ResearchBriefing/Summary/POST-PN-0563
 
Description Back from the Dead: Schools Events 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Exhibited at an event with the Museum of the History of Science for KS4 and KS5 study days that they ran alongside their exhibition about penicillin and antibiotics. Along with members of my lab group, we demonstrated several exhibitions which led to questions and discussions. The Education Officer at the Museum said that "feedback from the day was universally positive and there were very many comments from both staff and students who appreciated the range and diversity of the activities, but particularly the opportunity to meet and hear from 'real' scientists and researchers."
Year(s) Of Engagement Activity 2016
URL http://www.mhs.ox.ac.uk/back-from-the-dead/
 
Description Bacterial World Exhibition at the Oxford University Museum of Natural History 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I gave a talk on my research to the public at the Oxford University Museum of Natural History as part of their Bacterial World exhibition. I also demonstrated a microbiology-themed game that I created, The Phylogenetic Christmas Tree, at their Party in a Petri Dish Christmas event.
Year(s) Of Engagement Activity 2018
URL http://www.oum.ox.ac.uk/bacterialworld/
 
Description Soapbox Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I stood on a soapbox outside the Westgate Centre, a busy Oxford shopping centre, to promote the visibility of women in STEM as part of Soapbox Science. I spoke to passing members of the public about antibiotic resistance and my research.
Year(s) Of Engagement Activity 2018
URL http://soapboxscience.org/soapbox-science-2018-oxford/
 
Description Swab and Send at New Scientist Live 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I volunteered with Swab and Send, a public engagement initiative run by the Liverpool School of Tropical Medicine, which involves the general public in the process of antibiotic discovery at New Scientist Live 2018 in the London Excel arena, attended by 40000 members of the public. We gave away 800 swabs for people to use at home to try and discover new antibiotics. I also talked with many members of the public about my research.
Year(s) Of Engagement Activity 2018
URL https://www.lstmed.ac.uk/public-engagement/swab-send