Isomerase, with collaborators from leading industrial and academic institutions, including the University of Cambridge, John Innes Centre, Pfizer, Roche and DSTL, have published a paper titled “Diversity oriented biosynthesis via accelerated evolution of modular gene clusters” in Nature Communications. DOI 10.1038/s41467-017-01344-3

Dr Matthew Gregory, one of the corresponding authors and CEO of Isomerase Therapeutics Ltd., commented “We are delighted that this paper has been published in Nature Communications. It describes ground-breaking methods for generating broad natural product diversity which have the potential to help discover a vast array of completely new natural products in the polyketide chemical space. Polyketides include a large number of commercially successful natural products, such as rapamycin, erythromycin, amphotericin, spinosyn, monensin and rifamycin. Additionally, the learnings from this work are also helping us with targeted changes to this class of molecule. Whilst we have previously filed patent applications on the method, it is great to finally publish this work in a high impact peer reviewed journal.”

Professor Barrie Wilkinson of the John Innes Centre continued “The work described in this paper has important ramifications for the polyketide field. Not only is it a method that can rapidly generate new broad chemical diversity in a proven class, but it also mimics and accelerates the process that we believe is prevalent in natural polyketide evolution.”
This landmark paper describes the some of the synthetic biology techniques used to underpin an important element of Isomerase’s Evolution Engine® platform. This leading-edge discovery and development platform will combine the ability to generate unprecedented levels of natural products diversity with rapid screening to deliver highly targeted hits. The platform is designed to be used iteratively to rapidly optimise hits to deliver clinically relevant leads.

The abstract is as follows:

Erythromycin, avermectin and rapamycin are clinically-useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes.



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