Development of new tools for de novo polyketide synthase design

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Natural products are diverse chemical compounds, produced chiefly by bacteria and fungi, that confer a survival advantageon the producing strain often by antagonising the growth of competing organisms. Among such natural products,polyketides are a particularly successful drug class, with >40 marketed examples, the top six with peak annual sales of >$1billion. Many companies have tried to improve upon natural diversity, with limited success. Previous methods used toengineer polyketide synthases (PKS), the proteins which generate these products, can be slow, are complex to design, andhave frequently poorly productive and yielding.We aim to develop new synthetic biology tools for de novo syntheticgeneration of productive polyketide synthases (PKS), with broad potential for application in therapeutic discovery anddevelopment and in other areas where natural products have been successful.Researchers at our industrial partner Isomerase Therapeutics have discovered a groundbreaking technique for usingrecombination to rapidly generate novel and productive PKS. We believe that analysing these recombination events andidentifying potential recombination hotspots could lead to new tools and techniques for rational design of new polyketidenatural products. The Cambridge research team will use our extensive expertise in genome sequencing and analysis ofantibiotic-producing bacteria and collaborate with Isomerase to obtain genome sequence of up to 60 strains in whichrecombined PKS have been shown to give rise to novel truncated or elongated polyketide products. By careful sequencecomparisons between such rearranged PKS genes, we aim to establish the identity of those 'hotspot' regions in whichrecombination favours a successful outcome; and to establish the extent to which these hotspot regions vary betweendifferent PKS. This would open the way to the construction of an in silico database of PKS gene fragments defined byhotspot boundaries, a potentially valuable asset in the future design and construction of novel PKS from scratch.