About the Project
Rising antibiotic resistance is a major problem for human health. Resistance to β-lactams, the single most important antibiotic class, usually arises through their breakdown by β-lactamases (BLs). Many BL producing bacteria are multi-drug resistant and may cause untreatable infections. Worryingly, new BL variants conferring resistance are detected frequently. Several BLs that are currently distributed worldwide are from the BL classes A (KPC-2), B (NDM-1) and D (OXA-48). However, class C BLs are…
increasingly detected and involved in causing resistance against ‘last resort’ treatments such as the ceftazidime-avibactam (AviCaz) antibiotic-inhibitor combination therapy. We have previously shown that for serine BLs from classes A & D, structural and kinetic data combined with multi-scale computer simulations provides detailed insight into the molecular determinants of resistance-conferring activity (e.g. ACS Catal 2020, 2022; ACS Infect Disease 2022, JACS 2023, FEBS Lett 2025, JCIM 2026). Due to the relative lack of experimental data, obtaining such structure-activity relationships of clinically relevant Class C enzymes is still a challenge, although we have recently shown that similar insights are possible (Lima & Van der Kamp, ACS Catal 2025). This multidisciplinary project now aims to combine simulation, structure determination and enzyme kinetics to understand class C BL-driven resistance against key antibiotic treatments in detail.
The proposed project will focus on two key aspects: breakdown of cephalosporin beta-lactam antibiotics (BLAs) by class C BLs and the inhibition of class C BLs by diazabicyclooctanone (DBO) β-lactamase inhibitors (BLIs). These two together will determine the resistance that BLs will confer against ‘last resort’ BLA/BLI combination therapies. Throughout, computational and experimental work will be closely integrated. Computational analysis of crucial interactions, catalytic mechanisms, reaction intermediates and conformational behaviour (Van der Kamp) will test hypotheses and help analyse enzyme kinetics (Tooke, Spencer). X-ray crystallography (Tooke, Spencer) will provide the necessary structural data to verify initial hypotheses and allow additional computational modelling. The project will focus on a set of Class C BLs from both chromosomal and plasmid origin where changes in different regions have been shown to increase resistance. Initially, outstanding questions on the detailed mechanism will be addressed. Then, multiscale computational ‘assays’ will be designed to efficiently predict activity differences (by comparison to existing and new experimental data). This is likely challenging, as exact structures of the variants of interest in complex with the BLAs and BLIs are typically not available. Alongside using recent advances in AI structure prediction (e.g. AlphaFold3), structures of selected BL-BLA/BLI complexes will be determined experimentally (as these are often not predicted with sufficient accuracy by AI for new variants). Based on the information gained, we aim to predict new putative resistance-conferring BL variants from computational screening of mutations at key positions, and validate these predictions with experimental determination of beta-lactam hydrolysis and inhibition using steady-state, and state-of-the-art stopped- and quenched-flow kinetic methods, along with parallel investigation of antibiotic susceptibility in bacterial killing assays. The project will provide training in cutting-edge techniques in complementary disciplines (computational chemistry, molecular biology/biochemistry) using state-of-the-art facilities in the context of a highly collaborative AMR research environment. It will benefit from Bristol and GW4’s excellent resources for high-performance computing and access to X-ray facilities.
Mechanistic insights of Class C BL conferred antibiotic resistance can inform both the use of existing antibiotics and the possible development of new beta-lactam antibiotics to evade BL-mediated resistance. To accelerate knowledge transfer, findings will be discussed with our network of local, national and international collaborators prior to publication. We will also exploit the broad interest in antimicrobial resistance through public engagement activities.
How to Apply
A list of all the projects and how to apply is available on the GW4 BioMed website at gw4biomed.ac.uk. You may select up to 2 projects and submit one application per candidate only.
Please complete an application to the GW4 BioMed3 for an ‘offer of funding’. If successful, you will also need to make an application for an 'offer to study' to your chosen institution later.
Please complete the online application form linked from our website by 5.00pm on Wednesday, 21st October 2026. Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the GW4 BioMed website for details and updates. If you are shortlisted for interview, you will be notified from Tuesday, 22nd December 2026. Interviews will be held virtually on 26th and 27th January 2027. Studentships will start on 1st October 2027.
Further Information
For informal enquiries, please contact GW4BioMed@cardiff.ac.uk.
For project related queries, please contact the respective supervisors listed on the project descriptions on the GW4 BioMed website.
Funding Notes
These studentships are funded through GW4 BioMed3 MRC Doctoral Landscape Programme and consist of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£21, 805 p.a. for 2026/27, updated each year).
Additional research training and support funding of up to £5,000 per annum is also available.
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