This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Carbapenems are so-called ‘last-resort’ antibiotics used to treat multidrug-resistant infections caused by various bacterial pathogens. Carbapenem resistant Gram-negative bacteria, including Escherichia coli and Klebsiella pneumoniae, are increasing and these bacteria are among the most concerning causes of drug-resistant infections, for which there are only limited or no treatment options available. In the UK, the North West of England and London show the highest rates of carbapenem resistance and the UK Health Security Agency (UKHSA) reported Escherichia coli and Klebsiella pneumoniae posing the highest risk of all Gram-negative bacteria, with E. coli (34.8%) and K. pneumoniae (32.2 %) being responsible for 67% of all reported cases of bacterial species with acquired resistance to carbapenem (UKHSA, 2025). The main mechanism of resistance to carbapenems is the production of enzymes that hydrolyse the drug (carbapenemases). These enzymes are often found on plasmids, extra chromosomal mobile DNA, which can be transmitted horizontally to neighbouring cells, including to unrelated bacterial species and thereby accelerate the spread of resistance. New acquisition of resistance genes often imposes a fitness cost to the cell. This cost can be overcome by the strong selection pressure with antibiotics. In the absence of antibiotic selection, these genes can be lost; however, many resistance genes are maintained in the bacterial population even without antibiotic selection pressure. This is achieved through compensatory evolution, that increases fitness, or through mechanisms of persistence of mobile genetic elements, e.g. plasmid conjugation. There is a lack of understanding of the mechanisms that increase the stability of carbapenem resistance, and of how they are lost. The aim of this project is to understand the (in)stability of acquired carbapenem resistance in a set of clinical isolates of carbapenemase-producing E. coli and K. pneumoniae. This will be accomplished by investigating and quantifying resistance loss in these isolates under non-selective condition and by investigating the molecular mechanism of increased stability though compensatory evolution under carbapenem selection using experimental evolution and whole genomes sequencing. This project will leverage access to a large collection of contemporary carbapenem resistant isolates from clinical settings. |
| Where does this project lie in the translational pathway? | T1 - Basic Research,T2 - Human /Clinical Research |
| Methodological Aspects | Molecular and microbiological methods, bioinformatics, modelling, genomics and sequence data analysis. |
| Expected Outputs | Translatable knowledge about the stability and transmission of resistance to carbapenems, last-resort antibiotics. Peer-reviewed publications with the potential of high translational impact. Data generated for use in applications to generate further funding. PhD student will be encouraged and supported to apply for early career funding opportunities and developing a personal fellow ship application. |
| Training Opportunities | Training in microbiological and molecular biology methods, DNA sequencing (potential from DNA extraction, library preparation, sequencing on short-and long-read platforms and sequence analysis), genomics, bioinformatics and modelling. Data analysis. Scientific writing and publishing, presentation skills. |
| Skills Required | Enthusiasm for microbiology and antimicrobial resistance research. Background in molecular biology, microbiology and/or genomics would be advantageous but not essential. |
| Subject Areas | Resistance research and management |
| Key Publications associated with this project |
Duggan C, Brookfield C, Lawrie D, Owen V, Neal T, Cruise J, Fraser AJ, Graf FE, Cantillon D, Lewis JM, Edwards T, Heinz E. Multi-species blaNDM outbreak in multiple tertiary and a primary healthcare facility in Merseyside, UK, driven by a combination of multi-species plasmids and small clonal outbreaks. (2025). medRxiv: https://doi.org/10.1101/2025.05.09.25327284 Graf FE, Goodman RN, Gallichan S, Forrest S, Picton-Barlow E, Fraser AJ, Phan M, Mphasa M, Hubbard ATM, Musicha P, Schembri MA, Roberts AP, Edwards T, Lewis JM, Feasey NA. Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase producing Enterobacterales. (2024) Nature communications: https://doi.org/10.1038/s41467-024-53391-2 Lewis JM, Mphasa M, Banda R, Beale M, Heinz E, Mallewa J, Jewell C, Faragher B, Thomson NR, Feasey NA. Dynamics of gut mucosal colonisation with extended spectrum beta-lactamase producing Enterobacterales in Malawi. (2022) Nature Microbiology: 10.1038/s41564-022-01216-7 Alalam H, Graf FE, Palm M, Abadikhah M, Zackrisson M, Boström J, Fransson A, Mattsson M, Hadjineophytou C, Persson L, Stenberg S, Ghiaci P, Sunnerhagen P, Warringer J, Farewell A. A high-throughput method for screening for genes controlling bacterial conjugation of antibiotic resistance. mSystems. (2020). https://doi.org/10.1128/msystems.01226-20 |