Saving our last-line antimicrobials

An increasing number of pathogens have developed resistance mechanisms against beta-lactam (BL) antibiotics, most commonly by acquisition of genes that encode for enzymes de-activating the BLs, so-called beta-lactamases (BLAs). 

One tactic to counter this is to combine the BLs with inhibitors; small molecules that bind to the bacterial enzymes, rendering the bacteria de facto sensitive to the antimicrobial. However, an increasing number of bacteria are able to counter the BL + inhibitor combinations by increasing the expression of their BLAs. This project will focus on understanding these mechanisms, which can be a combination of strong promoters causing increased gene expression, increase of the gene copy number either via increased numbers of a plasmid or by duplications of the gene itself through the mobile elements it is enclosed by. There are also potentially other changes in the overall regulatory network that remain unclear. New last resort BL + inhibitor combinations have been recently approved, and it is unclear whether resistance to these last-line antimicrobials will also occur in pathogenic bacteria via similar mechanisms. You will use a combination of laboratory experiments and bioinformatics to disentangle the different strategies used by clinical isolates of the Gram-negative pathogens Escherichia coli and Klebsiella pneumoniae, analyse the genomic context and population genomics to understand their spread and transmission of this mechanism, and targeted transcriptomics to investigate the impact of these mechanisms on the whole regulatory network and the bacteria’s fitness. A translational question specifically addressed will be if an increase of the inhibitor concentration, or the use of other antibiotics in combination can counter some or all of these regulatory resistance mechanisms. This would be a comparatively straightforward change in treatment regimen that could potentially rescue the use of the relevant BLs for the respective resistance mechanisms. 

Where does the project lie on the Translational Pathway?

T1 – Basic 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 TE and EH 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 a programmer in industry. Recent work from TE and EH on multidrug-resistant bacterial population dynamics has resulted in high-impact publications in Genome Biology, Nature Communications and Microbial Genomics. The project will provide the unique opportunity to work on highly relevant clinical questions by a closely linked combination of computational and laboratory methods to understand the resistance dynamics of some of the most relevant Gram-negative opportunistic pathogens, in particular Escherichia coli and Klebsiella pneumoniae. There is clear scope for translational impact, with the project potentially providing evidence for improved or resistance blocking treatment regimens, and the potential to uncover diagnostic targets.  The student will furthermore be embedded in the larger collaborative network on opportunistic Gram-negative pathogens, which includes Prof. Corander (associate faculty at Wellcome Sanger Institute, faculty at University of Oslo and University of Helsinki), Dr. Cornick (group leader at UoL/MLW) and Abhilasha Karkey (associate professor Oxford University, leader of the Nepal clinical research unit).   This is a key strategic area for LSTM as evidenced by the recent appointment of TE on career track this year and EH who was recruited from the prestigious Wellcome Sanger Institute, rapidly passed career track, and was promoted to senior lecturer following her first 12-months tenure review.

Training Opportunities

Training in cutting edge pathogen bioinformatics will be provided by EH, who is a world leader in this field. Training in molecular techniques and microbiology will be provided by the TE lab, where these procedures are well established. The student will be able to attend courses on sequencing library preparation and nanopore sequencing ran by Oxford Nanopore. We will encourage the student to identify both internal and external training opportunities that are of interest and will support their attendance.

Skills Required

General microbiology and bioinformatics background

Key Publications associated with this project

Hubbard, A., Mason, J., Roberts, P., Parry, C., Corless, C., van Aartsen, J., Howard, A., Fraser, A., Adams, E., Roberts, A., Edwards, T. (2020). Piperacillin/tazobactam resistance in a clinical isolate of Escherichia coli due to IS26-mediated amplification of blaTEM-1B. Nature Communications. 11:4915 DOI: 10.1038/s41467-020-18668-2

Edwards, T., Heinz, E., van Aartsen, J., Howard, A., Roberts, P., Corless, C., Fraser, A., Williams, C.T., Bulgasim, I., Cuevas, L.E., Parry, C.M., Roberts, A.P., Adams, E.R., Mason, J., Hubbard, A. (2020). Piperacillin/tazobactam resistant, cephalosporin susceptible Escherichia coli bloodstream infections driven by multiple resistance mechanisms across diverse sequence types. BioRxiv doi: https://doi.org/10.1101/2020.09.18.302992 [PREPRINT]

2019      Heinz E, Ejaz H, Bartholdson-Scott J, Wang N, Gujaran S, Pickard D, Wilksch JJ, Cao H, ul-Haq I, Dougan G, Strugnell RA. Resistance mechanisms and population structure of highly drug-resistant Klebsiella in Pakistan during the introduction of the carbapenemase NDM-1. Scientific Reports. doi: 10.1038/s41598-019-38943-7

2019      Ellington MJ*, Heinz E* (*Equally contributing), Wailan A, Dorman M, Cain A, Henson S, Gleadall N, Brown NM, Woodford N, Parkhill J, Török EM, Peacock SJ, Thomson NR. Contrasting patterns of longitudinal population dynamics and antimicrobial resistance mechanisms in two priority bacterial pathogens over 7 years in a single center. Genome Biology. doi: 10.1186/s13059-019-1785-1.

Papp-Wallace, K.M. (2019). The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections. Expert Opin Pharmacother. 20(17): 2169–2184. doi:10.1080/14656566.2019.1660772

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