Combinatorial biosynthesis of polyketides — a perspective

Since their discovery, polyketide synthases have been attractive targets of biosynthetic engineering to make ‘unnatural’ natural products. Although combinatorial biosynthesis has made encouraging advances over the past two decades, the field remains in its infancy. In this enzyme-centric perspective, we discuss the scientific and technological challenges that could accelerate the adoption of combinatorial biosynthesis as a method of choice for the preparation of encoded libraries of bioactive small molecules. Borrowing a page from the protein structure prediction community, we propose a periodic challenge program to vet the most promising methods in the field, and to foster the collective development of useful tools and algorithms.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (140 K)Download as PowerPoint slideHighlights► New PKS gene clusters are being identified at an explosive rate. ► Understanding of PKS chemistry has improved, but its implications remain untested. ► DNA assembly of hybrid PKSs is easier than before, but heterologous expression and product analysis remain challenging. ► A CASP-like competition could propel combinatorial biosynthesis into mainstream engineering.