Biosynthesis and exploitation of marine-derived post-translationally modified ribosomal peptides

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Compounds from Nature are still a mainstay for drug discovery and in certain therapeutic areas such as cancer, 70% of drugs used in the clinic are of natural origin. Many of these compounds are highly complex and are difficult to re-create in the laboratory. A recent trend has been to try to understand the mechanisms the organisms use to biologically synthesise these molecules. This work is already in a very advanced stage for certain classes of these molecules, which are constructed from small subunits, and are known as polyketides and non-ribosomal peptides. Candidates from each category are already in the clinic, or are being tested on patients to assess their suitability as pharmaceuticals. In some cases the supply from nature is limited, and the organism's processes have been transplanted into easy-to-culture bacteria, which then produces the compound of interest. This is done by taking the DNA which encodes the instructions (the biosynthetic genes) to make the compounds and introducing these into a bacterium. This method has been successfully used to produce prospective drug candidates and to engineer new compounds by changing the instructions. We have recently discovered that potential anti-lymphoma compounds, originally isolated from a marine invertebrate (seasquirt) are in fact produced by its bacterial symbiont, Prochloron. Its instructions for biological synthesis of the compounds are encoded in a much more straightforward way than the classes of compounds mentioned above, and should make it possible to modify them more readily. This class of compounds is relatively unexplored, but evidence from the scientific literature suggests that there may be many more examples of this class of compound in certain types of marine invertebrate. Using the known chemical structure we can predict the way in which it is encoded in the DNA of the producing organism, and thus locate the relevant biosynthetic genes. We will chemically screen a number of target marine invertebrates (seasquirts, sponges) and extract their DNA. After this we will then screen the DNA for the presence of the relevant biosynthetic genes and determine the sequence of their DNA. Doing this on a number of species producing this unusual group of compounds will allow us to understand the rules by which these compounds are synthesised within the organisms. The combined information can then be used to screen marine invertebrates, which are suspected, but not known to, produce similar compounds. Combining this approach with ecological information will enable us to identify organisms, which are likely to produce other compounds of this type with potent biological activity. The outcomes of this work will be the discovery of new biologically active compounds from marine invertebrates together with methods to produce them in a sustainable fashion and modify them to modulate their activity. The method necessitates only a small specimen to be collected for DNA extraction, rather than large scale harvesting. In addition we will gain an understanding of how these unique compounds are biologically synthesised in these primitive organisms.