Tracking mobile resistance mechanisms and the host organisms to disentangle the movement of resistance within a human high-risk population

Antimicrobial resistance is one of the most urgent threats to global public health and endangers our ability to safely perform invasive medical procedures, which rely on our ability to prevent bacterial infections. Intense research over the past decades has clearly shown that resistance will inevitably evolve against chemical interventions, and that the spill-over of chemicals into the environment exacerbates the selection for more resistant bacteria. It is thus highly relevant that we identify the major hotspots for transmission, and the impact of presence of resistance elements in the gut on subsequent infections in patients.

The dynamics of opportunistic Gram-negative bacterial pathogens are highly complex, as they are also found as (presumably) harmless colonizers of the human gut, as well as capable of surviving in natural and built environments given their extensive metabolic potentials and ability to form biofilms. Your project will be linked to a large study trying to follow transmission of mobile resistance elements, their host cells, and whether movement of resistance elements between strains or species is a yet underappreciated but main factor of risk of subsequent infection with multidrug-resistant Gram negative bacteria, in particular Escherichia coli and Klebsiella pneumoniae.

You will use long- and short-read sequencing and subsequent data analysis, combined with selection of bacteria and resistance elements using different growth media (selecting for resistant bacteria, and selecting for all members of the species), and state-of-the-art computational methods, to track the movement of mobile elements associated with particular lineages as well as their movement across different lineages and species. This will provide us highly relevant insights into the dynamics of spread of multidrug-resistant bacteria causing difficult-to-treat infections, and whether current protocols used for surveillance or outbreak tracking (often focused on selecting for resistant organisms) are missing an important step in the dynamics of the spread of resistance. 

Where does the project lie on the Translational Pathway?

T1 – Basic Research, T2 – Human/Clinical Research

Expected Outputs

The project will produce high quality REF returnable 3*/4* publications and will provide the evidence base for large scale research council funding in a global priority area. Previous and current PhD students from the supervisor team have all published one or several high-quality first-author papers, including Molecular Microbiology, PLoS Pathogens, Microbial Genomics and Nucleic Acids Research, and have all moved to postdoctoral positions or are working as programmers in industry.

 

There is clear scope for translational impact, and there is a strong interest in antimicrobial resistance research from funders and public health institutions. Targeting multi-drug resistance is a key strategic area for LSTM as evidenced by the recruitment of EH from the Wellcome Sanger Institute who was confirmed for tenure in the first year of her Career Track followed by promotion to Senior Lecturer and TE who was recently promoted to join the Career Track scheme.

Training Opportunities

The student will receive a highly sought-after combination of skills in i) bioinformatics, including comparative genomics and molecular evolution, and ii) molecular biology, both basic and clinical microbiology. This will provide a comprehensive set of skills to address this as well as future questions in the field of bacterial pathogens, in particular multidrug-resistant opportunists, which is one of the main threats of public health world-wide.

Skills Required

Basic knowledge of and strong interest in bioinformatics, microbiology and immunology.

Key Publications associated with this project

2021      Bacterial genomic epidemiology with mixed samples. Tommi Mäklin, Teemu Kallonen, Jarno Alanko, Ørjan Samuelsen, Kristin Hegstad, Veli Mäkinen, Jukka Corander, Eva Heinz, Antti Honkela. Microbial Genomics Nov;7(11) doi: 10.1099/mgen.0.000691

2021      Dynamics of gut mucosal colonisation with extended spectrum beta-lactamase producing Enterobacterales in Malawi. Joseph M. Lewis, Madalitso Mphasa, Rachel Banda, Mathew A. Beale, Eva Heinz, Jane Mallewa, Christopher Jewell, Brian Faragher, Nicholas R. Thomson, Nicholas A Feasey. Preprint medRXiv doi: https://doi.org/10.1101/2021.10.08.21264775

2021     Piperacillin/tazobactam resistant, cephalosporin susceptible Escherichia coli bloodstream infections are driven by multiple acquisition of resistance across diverse sequence types. Thomas Edwards, Eva Heinz, Jon van Aartsen, Alex Howard, Paul Roberts, Caroline Corless, Alice J. Fraser, Christopher T. Williams, Issra Bulgasim, Luis E. Cuevas, Christopher M. Parry, Adam P. Roberts, Emily R. Adams, Jenifer Mason, Alasdair T. M. Hubbard. Preprint bioRXiv doi: https://doi.org/10.1101/2020.09.18.302992

2021      Genomic investigation of a suspected Klebsiella pneumoniae outbreak in a neonatal care unit in sub-Saharan Africa. Jennifer Cornick, Patrick Musicha, Chikondi Peno, Ezgi Seager, Pui-Ying Iroh Tam, Sithembile Bilima, Aisleen Bennett, Neil Kennedy, Nicholas Feasey, Eva Heinz, Amy K Cain. Microbial Genomics Nov;7(11). doi: 10.1099/mgen.0.000703

2019       rPinecone: Define sub-lineages of a clonal expansion via a phylogenetic tree

Alexander M Wailan, Francesc Coll, Eva Heinz, Gerry Tonkin-Hill, Jukka Corander, Nicholas A Feasey, Nicholas R Thomson. Apr;5(4):e000264. doi: 10.1099/mgen.0.000264

Now Accepting Applications 

CLOSING DATE FOR APPLICATIONS: Application Portal closes: Wednesday 9th February 2022 (12:00 noon UK time)

Shortlisting complete by: End Feb/early March 2022

Interviews by: Late March/early April 2022

For more information on Eligibility, funding and how to apply please visit the MRC DTP/CASE pages