Analysis and Exploitation of Oxygen-Dependent Modification to Ribosomes

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Ribosomes are intracellular machines that make proteins, but they also contain proteins. Recent BBSRC funded work led to the discovery that ribosomal proteins undergo a modification, termed hydroxylation, dependent on atmospheric oxygen at sites of importance for protein biosynthesis. One of the largest classes of antibiotics, e.g. erythromycin, targets ribosomes. Point mutations to ribosomes confer resistance to such antibiotics. Hence it should be possible to develop compounds that selectively target unmodified over modified ribosomes. Tumour cells are often hypoxic so should contain ribosomes that are ales hydroxylated than normal cells. We propose to use Follow on Funding to test synthetically modified antibiotics (guided by ribosome structures) to identify compounds that selectively inhibit unmodified over modified (or vice versa) ribosomes. The results will be used to support patent applications and, if appropriate, to form a spin-out company.