This project is one of a number that are in competition for funding from the NERC Great Western Four+ Doctoral Training Partnership (GW4+ DTP). The GW4+ DTP consists of the Great Western Four alliance of the University of Bath, University of Bristol, Cardiff University and the University of Exeter plus five Research Organisation partners: British Antarctic Survey, British Geological Survey, Centre for Ecology and Hydrology, the Natural History Museum and Plymouth Marine Laboratory. The partnership aims to provide a broad training in earth and environmental sciences, designed to train tomorrow’s leaders in earth and environmental science. For further details about the programme please see http://nercgw4plus.ac.uk/
Dr Michiel Vos, University of Exeter Medical School
Dr William Gaze - University of Exeter Medical School
Professor Angus Buckling - Biosciences, University of Exeter
Prof Edward Feil, Milner Centre for Evolution, Department of Biology & Biochemistry, University of Bath
The dramatic increase in antimicrobial resistance (AMR) forms a global challenge to public health. It is increasingly understood that the natural environment plays a key role in AMR evolution. Pharmaceutical residues and other pollutants in the environment such as metals can select for AMR. Moreover, largescale mixing of human-associated- and environmental bacteria can promote the exchange of resistance genes between strains, providing the genetic substrate for selection. Recent work suggests that such horizontal gene transfer might occur at the same rate as mutation but the relative importance of these two fundamentally distinct genetic mechanisms in generating AMR is not known. In this PhD project, we will design experiments to quantify and compare the prevalence of point mutations versus horizontal gene transfer events in generating resistance. Using flow cytometry and genome sequencing, we will measure the type and rate of genetic change under different realistic pollution scenarios. These data will provide fundamental data on bacterial genome evolution but also provide a scientific basis for pollution management.
Project Aims and Methods:
The main aim is to combine antibiotic selection with whole-genome re-sequencing in a bacterial pathogen to identify the prevalence of distinct genetic mechanisms (horizontal gene transfer versus (vertical) point mutations) responsible for resistance. Specifically:
1. Antibiotic selection takes place in a continuum from high therapeutic concentrations down to much lower concentrations in the environment. As the costs of AMR mutations are assumed to be generally lower than the cost of carriage of introduced genes, it is hypothesized that the latter type of resistance evolution is more prevalent under higher antibiotic concentrations. We will vary antibiotic concentrations to alter the cost of resistance enabling us to measure the prevalence of mutation-based relative to horizontal gene transfer-based AMR.
2. The uptake of genes is crucially dependent on access to community diversity. Bacteria usually do not live in isolation but are embedded in complex microbiomes. We will test whether resistance evolution via lateral gene transfer is promoted in more diverse microbiomes relative to mutation by varying species diversity in experimental microcosms.
The student will be encouraged to co-develop experiments and analyses.
The student will work in state-of-the-art microbiology labs at the ESI building at the University of Exeter’s Penryn campus where MV, AB and WGs groups are based. Having three local supervisors and their group members will allow efficient knowledge transfer and training in a wide range of skills, including microbiology, genomics and statistics. EFs group is based in the Milner Centre for Evolution at the university of Bath with >20 PI’s in big data science, genomics and informatics which the student will have the opportunity to visit in addition to contact via email and skype. MV and WG are part of the European Centre for Environment and Human Health (ECEHH) which has a mission to disseminate its research via the distribution of videos, interviews and press releases from which the project and student can greatly benefit. MV and WG have contributed to a Wellcome Trust-funded exhibition on gut microbiomes “Invisible You” at the Eden Project providing further opportunities to engage with the public. The student will be encouraged to participate in the wide range of professional development opportunities available at the University of Exeter (http://as.exeter.ac.uk/rdp/researchstaff/
) to further career development.
References / Background reading list:
Murray, A., Zhang, L., Yin, X., Zhang, T., Buckling, A., Snape, J. and Gaze, W., 2018. Novel insights into selection for antibiotic resistance in complex microbial communities. bioRxiv, p.323634.
Richardson, E.J., Bacigalupe, R., Harrison, E.M., Weinert, L.A., Lycett, S., Vrieling, M., Robb, K., Hoskisson, P.A., Holden, M.T., Feil, E.J. and Paterson, G.K., 2018. Gene exchange drives the ecological success of a multi-host bacterial pathogen. Nature ecology & evolution, 2(9), p.1468.
Vos, M., Hesselman, M. C., te Beek, T. A., van Passel, M. W., & Eyre-Walker, A. (2015). Rates of lateral gene transfer in prokaryotes: high but why? Trends in microbiology, 23(10), 598-605.
Wielgoss, S., Didelot, X., Chaudhuri, R. R., Liu, X., Weedall, G. D., Velicer, G. J., & Vos, M. (2016). A barrier to homologous recombination between sympatric strains of the cooperative soil bacterium Myxococcus xanthus. The ISME journal.
Wellington, E.M., Boxall, A.B., Cross, P., Feil, E.J., Gaze, W.H., Hawkey, P.M., Johnson-Rollings, A.S., Jones, D.L., Lee, N.M., Otten, W. and Thomas, C.M., 2013. The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria. The Lancet infectious diseases, 13(2), pp.155-165.