Discovery and Function of Natural Metalloprotease Inhibitors
Bacteria have evolved the ability to produce natural products with potent bioactivities, which makes these compounds excellent candidates as medicines and agrochemicals. In particular, the majority of clinically useful antibiotics come from bacteria. However, molecule rediscovery poses a problem in the search for new medicines from natural sources, while the development of antimicrobial resistance is a major problem for both existing and new antimicrobials. Genome mining represents a promising strategy to identify new molecules. Here, genomic data is used to identify pathways that are predicted to make novel compounds. Specific genetic features can be used to prioritise pathways that are predicted to make new molecules with useful biological activities.
This project will focus on a class of molecules that inhibit metalloproteases, which are promising targets for antibiotic discovery, as well as multiple other diseases. The PhD student will use genomic data to discover new natural products and then understand how their targets are either sensitive or resistant. Understanding the mechanisms of activity and resistance could help better design antibiotics in the future. The project will span microbiology, genetics, mass spectrometry, natural product chemistry and biochemistry. This multidisciplinary project will be based in the laboratory of Dr Andrew Truman in the Department of Molecula Microbiology at the John Innes Centre, which has world-class facilities for bacterial genetics and natural product biosynthesis. Further expertise is provided by secondary supervisor Prof. Barrie Wilkinson (John Innes Centre), who is an expert in studying the biosynthesis and mechanism of action of antibiotics. This project provides an exciting opportunity to discover new bioactive molecules and develop skills across biology and chemistry, including the purification and structural elucidation of natural products. Applications are welcomed from students who are excited to work on a multidisciplinary project across the biological and chemical sciences.
References
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Moffat, A. D., Höing, L., Santos-Aberturas, J., Markwalder, T., Malone, J. G., Teufel, R. & Truman, A. W. Understanding the biosynthesis, metabolic regulation, and anti-phytopathogen activity of 3,7-dihydroxytropolone in Pseudomonas spp. bioRxiv (2024). doi:10.1101/2024.04.03.587903
Booth, T. J., Bozhüyük, K. A. J., Liston, J. D., Batey, S. F. D., Lacey, E. & Wilkinson, B. Bifurcation drives the evolution of assembly-line biosynthesis. Nat. Commun. 13, 3498 (2022).
Eyles, T. H., Vior, N. M., Lacret, R. & Truman, A. W. Understanding thioamitide biosynthesis using pathway engineering and untargeted metabolomics. Chem. Sci. 12, 7138–7150 (2021).