GW4 BioMed3 MRC DLP PhD project: Designing Cell-Accumulating Covalent Inhibitors to Combat Gram-Negative Antimicrobial Resistance

About the project

About the Project This project is one of several in competition for funding from the GW4 BioMed3 MRC Doctoral Landscape Programme (DLP), which is offering up to 17 studentships for entry in September 2027. The partnership brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found on the DLP’s website . Please note that the application process may close early to either home or international candidates (or both) before the stated deadline if an unprecedented number of applications are received – check the DLP’s website for details and updates. Supervisory Team: Dr Scott Lovell (University of Bath) Dr Maisem Laabei (University of Bristol) The Project : Background: Antimicrobial resistance is a major global health threat, with Gram-negative bacteria posing a particular challenge because their outer membrane and efflux pumps prevent many compounds from reaching intracellular targets. Recent studies have identified physicochemical features that promote Gram-negative accumulation, including molecular rigidity and appropriately positioned ionisable amines, but these principles have largely been explored for reversible inhibitors. In parallel, covalent inhibitors can provide prolonged target engagement, increased potency and access to challenging proteins. Very little is known about how to design covalent inhibitors that efficiently accumulate within Gram-negative bacteria. This PhD will address this gap using the essential cell-wall biosynthesis enzyme MurA as a model intracellular target. MurA contains a chemically validated ligandable cysteine, Cys115, which is covalently modified by fosfomycin. It therefore provides an ideal system to determine whether rationally designed covalent compounds can enter Gram-negative bacteria, overcome permeability and efflux barriers, and irreversibly engage an intracellular target. Objective 1: Development of a Gram-negative accumulating covalent library. The project will develop an acrylamide-containing library based on commercially available rigid amino-acid scaffolds and diverse amines. Each compound will retain features associated with Gram-negative accumulation, including rigidity and a primary ionisable amine, while systematically varying ring topology, stereochemistry and the three-dimensional presentation and steric environment of the amine. This will directly test whether reduced steric congestion around the primary amine improves bacterial accumulation and intracellular target engagement. Direct-to-biology workflows developed in the Lovell laboratory will enable rapid parallel synthesis and screening. Objective 2: Biochemical validation of MurA covalent target engagement. Recombinant E. coli MurA will be expressed and purified to establish a biochemical screening platform. Compounds will be screened using enzyme activity assays, with time-dependent inhibition used to prioritise putative covalent inhibitors. Hits will be validated by intact-protein mass spectrometry, and a C115A MurA mutant will determine whether inhibition depends on the known ligandable cysteine. Objective 3: Defining permeability, efflux and intracellular target engagement. Lead compounds will then be evaluated in genetically defined E. coli strains, including wild-type cells, the outer membrane-permeable imp4213 mutant and a ΔtolC efflux-deficient mutant. Growth inhibition and MIC assays will establish whole-cell activity. Competitive activity-based protein profiling will then determine whether antibacterial activity results from productive intracellular MurA engagement. Cells pre-treated with lead compounds will be labelled with a broad-spectrum cysteine-reactive iodoacetamide probe, enabling quantitative chemoproteomic measurement of MurA Cys115 occupancy alongside proteome-wide off-target engagement. Comparison across the three strains will distinguish permeability-, efflux- and target-affinity-limited compounds. Outcomes and student ownership: The project will establish design principles for cell-accumulating covalent inhibitors in Gram-negative bacteria, defining how scaffold topology, stereochemistry and primary-amine presentation influence accumulation, efflux susceptibility and productive intracellular target engagement. The resulting chemical library, screening cascade and chemoproteomic workflow will provide a platform for broader antibacterial covalent drug discovery. The student will receive interdisciplinary training in medicinal chemistry, microbiology and chemical biology, with substantial scope to shape the project. Potential directions include improved bacterial accumulation assays, quantitative modelling of structure-accumulation relationships, detailed biochemical characterisation of MurA inhibition, or expansion to other intracellular antibacterial targets such as FabH, FabA and DsbA. Requirements: Applicants must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second-class degree will only be considered if they have a grade of Merit or above in a master’s degree. Academic qualifications are considered alongside significant relevant non-academic experience. Non-UK applicants will also be required to have met the English language entry requirements of the University of Bath. Enquiries and Applications: Informal enquiries are welcomed and should be directed to Dr Lovell: sdl35@bath.ac.uk Formal applications must be submitted direct to the GW4 BioMed3 DLP using their online application form . A list of all the projects and details on how to apply are available DLP’s website . You may apply for up to 2 projects and submit one application per candidate only. APPLICATIONS CLOSE AT 17:00 (GMT) ON 21 OCTOBER 2026. IMPORTANT: You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application for an offer of study from Bath. Equality, Diversity and Inclusion: We value a diverse research environment and aim to be an inclusive university, where difference is celebrated and respected. We welcome and encourage applications from under-represented groups. If you have circumstances that you feel we should be aware of that have affected your educational attainment, then please feel free to tell us about it in your application form. The best way to do this is a short paragraph at the end of your personal statement.

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