Project ID BE-MI2023_11

ThemeBE-MI

Co Supervisor 1A Chemistry, NMESWebsite

Co Supervisor 1B School of Biomedical Engineering & Imaging SciencesWebsite

Bacterial Siderophores as Tools for Diagnostic Imaging 

Scientific basis: Multi-drug resistant bacterial pathogens are frequent causes of hospital acquired infections which are often difficult to diagnose and treat. Pathogenic bacteria produce and small molecules with high iron affinity (Kaff >1025) known as “siderophores”.

Siderophores form iron complexes which are recognised and actively transported into the cell via dedicated, ligand-gated receptors/transporters. This mode of iron acquisition plays vital roles in pathogenicity and maintaining balance in the microbiome.

Diagnostic imaging with whole-body Positron Emission Tomography (PET) uses receptor-targeted radiotracers to localise diseased or infected tissue. PET is highly sensitive. This project will exploit the exquisite selectivity of siderophores to develop a radiolabelled siderophore complex as a diagnostic radiotracer for whole body imaging of bacterial infection.

Aims: We will utilise a novel fluorescent siderophore to specifically target pathogenic Gram-negative bacteria to:

1) distinguish between pathogenic and non-pathogenic bacteria;

2) understand the uptake mechanism;

3) fluorescence enable whole-body infection imaging via PET.

Techniques and skills: microbiology, fluorescence imaging, protein biochemistry, radiochemistry, small animal PET imaging

PhD Objectives:

Year 1: Investigate the uptake and selectivity of fluorescent siderophores in mixed bacterial populations. Undertake radiolabelling of siderophore and assess uptake in bacterial populations.

Year 2: Investigate uptake selectivity via microbiology and protein biochemistry. We are collaborating with Mark Sutton (HSE) to test clinical isolates. We will also investigate the specific siderophore receptor to understand uptake as a future antibiotic target.

Year 3: Undertake PET imaging of bacterial infections in mouse models using radiolabelled siderophore.

Year 4: Thesis / paper preparation and final experiments.

One representative publication from each co-supervisor:

G. Perez-Ortiz, J. Sidda, E. De Los Santos, C. B. Hubert, S. M. Barry In vitro Elucidation of the Crucial but Complex Oxidative Tailoring Steps in Rufomycin Biosynthesis, Enable One Pot Conversion of Rufomycin B to Rufomycin C Chem Commun. 2021, 57, 11795 – 11798

I. N. Hungnes, F. Al Salemee, P. J. Gawne, T. Eykyn, R. A. Atkinson, S. Y. A. Terry, F. Clarke, P. J. Blower, P. G. Pringle, M. T. Ma, One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for 99mTc radiolabelling of peptides. Dalton Trans. 2021, 50, 16156 – 16165.