Nature has the ability to make vast numbers of bioactive compounds with the instructions for making these molecules inside their DNA, referred to as Biosynthetic Gene Clusters or CGC’s. These compounds are all bioactive and far more complex than can be created with synthetic chemistry. The microbial domain signifies 90% of all natural diversity, however less than 1% has been discovered. Meanwhile, more than 40% of all therapeutics today are based on natural products.
Much research has been devoted to finding ways to activate silent BGCs but most are labour intensive and unreliable, requiring cluster by cluster manipulation. The “holy grail” for this research has been an efficient and scalable technology for activating cryptic BGCs from cultured and ideally uncultured organisms.
Demuris has developed a technology platform that will revolutionise this process. We have first cracked the problem of cloning and manipulating the large DNA segments that are needed to carry full length BGCs. The technology is completely scalable, enabling us to activate BGCs from random DNA segments of known organisms or even completely unknown organisms of environmental origin. The technology will enable us to provide libraries producing huge numbers of unscreened molecules for screening against any therapeutic target.
Demuris synthetic biology tools allow us to improve the drug-like properties of natural compounds. Biosynthetic Gene Clusters within microorganisms produce metabolites which can be manipulated in a combinatorial fashion to produce new derivatives. These derivatives can be entirely new chemical scaffolds and also compounds that have properties similar to current human medicines with improved drug properties.
The Demuris platform leverages breakthroughs in next-generation sequencing, genome editing, molecular biology, and protein engineering tools to create these novel derivatives. This powerful tool box allows us to rapidly advance hits and Lead compounds down the development pipeline.
Demuris owns one of the world’s most valuable collections of actinomycete bacteria – source of the majority of natural product based drugs. This collection allows us to find hosts for production and to create analogues of natural compounds. The Demuris collection was assembled by the leading actinomycete taxonomist, Prof Mike Goodfellow, who spent much of his 40 year career carrying out definitive taxonomic studies on these unusual and often difficult to culture organisms. The collection came from sources all over the world and from a wide range of habitats, involving about 200 man years of work. Much of it predates the restrictive Rio and Nagoya conventions. A large majority of the strains have been characterized in detail and data about each strain is recorded in a vast relational database. Demuris is currently sequencing the whole collection to enable rapid, in silico dereplication of screening hits, identification of analogue producers and potential production strains.
Demuris has a major collection of fungal inhibitors and has carried out a major project to characterise the mode of action of the inhibitors in collaboration with Prof Sir Paul Nurse (Lewis et al., 2018). Among a collection of cell cycle modulators, Demuris has identified a novel inhibitor of FOXO transcription factors, important targets for various cancers. The compound has low nanomolar activity against a range of human cancer cell lines, and is being developed in collaboration with the Northern Institute for Cancer Research, which has successfully developed several currently-marketed cancer drugs.
Demuris has discovered and characterised several new natural analogues of the ansamycin antibiotic Rifamycin (e.g. Mosei et al., 2018). Rifamycins are first line drugs against tuberculosis and are used in several other infectious disease therapies, but they suffer from antibiotic-resistance, especially Multi-drug resistant TB. The novel Demuris ansamycins have activity against MDR-TB and generally do not suffer from the resistance problems of Rifamycins. Optimised novel ansamycins have the potential to become front line new drugs for several infectious disease indications.
Ansamycins may have applications in other therapeutic areas, such as neurodegeneration. There is clinical evidence for potential efficacy in these major diseases with unmet therapeutic need, and Demuris is uniquely placed to deliver optimised drugs of this class.
Mitochondrial deficiency is being recognised as responsible for a wide range of congenital and degenerative diseases. Working with the Wellcome Mitochondrial Research Centre, Demuris has identified compounds that stimulate mitochondrial production. These compounds have the potential for use in treatments for multiple serious mitochondrial deficiency syndromes.
Demuris has major expertise in the anti-infective space, based on its origins in the Centre for Bacterial Cell Biology. Although the market for anti-infectives is presently difficult, we believe that it is only a matter of time before suitable incentives are put in place to reinvigorate the space. Demuris has a large number of diverse early stage assets in both antibacterials and antifungals.
Mosaei H, Molodtsov V, Kepplinger B, Harbottle J, Moon CW, Jeeves RE, Ceccaroni L, Shin Y, Morton-Laing S, Marrs ECL, Wills C, Clegg W, Yuzenkova Y, Perry JD, Bacon J, Errington J, Allenby NEE, Hall MJ, Murakami KS, Zenkin N (2018) Mode of action of kanglemycin A, an ansamycinnatural product that is active against rifampicin-resistant Mycobacterium tuberculosis. Molecular Cell 72, 263-274.
Kepplinger B, Morton-Laing S, Seistrup KH, Marrs ECL, Hopkins AP, Perry JD, Strahl H, Hall MJ, Errington J, Allenby NEE. (2018) Mode of action and heterologous expression of the natural product antibiotic vancoresmycin. ACS ChemBiol. 13, 207-214.
Lewis R, Li J, Allenby NEE, Errington J, Hayles J, Nurse PM. (2017) Screening and purification of natural products from Actinomycetes that affect cell shape of the fission yeast Schizosaccharomyces pombe. J Cell Science 130, 3173-3185.
Tyler AR, Mosaei H, Morton S, Waddell PG, Wills C, McFarlane W, Gray J, Goodfellow M, Errington J, Allenby N, Zenkin N, Hall MJ. (2017) Structural reassignment and absolute stereochemistry of Madurastatin C1 (MBJ-0034) and the related aziridine siderophores: Madurastatins A1, B1, and MBJ-0035. J Nat Prod. 80, 1558-1562.
Baksh A, Kepplinger B, Isah HA, Probert MR, Clegg W, Wills C, Goodfellow M, Errington J, Allenby N, Hall MJ. (2017) Production of 17-O-demethyl-geldanamycin, a cytotoxic ansamycin polyketide, by Streptomyces hygroscopicus DEM20745. Nat Prod Res. 31, 1895-1900.
Emami K, Guyet A, Kawai Y, Devi J, Wu LJ, Allenby N, Daniel RA, Errington J. (2017) RodA as the missing glycosyltransferase in B. subtilis and discovery of a novel antibiotic for the peptidoglycan polymerase pathway. Nature Microbiology 2, 16253.