GenoChemetic Strategy for Derivatization of the Violacein Natural Product Scaffold

Natural products
and their analogues are often challenging to synthesize
due to their complex scaffolds and embedded functional groups. Solely
relying on engineering the biosynthesis of natural products may lead
to limited compound diversity. Integrating synthetic biology with
synthetic chemistry allows rapid access to much more diverse portfolios
of xenobiotic compounds, which may accelerate the discovery of new
therapeutics. As a proof-of-concept, by supplementing an Escherichia
coli strain expressing the violacein biosynthesis pathway
with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase
RebH in vivo, six halogenated analogues of violacein
or deoxyviolacein were generated, demonstrating the promiscuity of
the violacein biosynthesis pathway. Furthermore, 20 new derivatives
were generated from 5-brominated violacein analogues via the Suzuki–Miyaura
cross-coupling reaction directly using the crude extract without prior
purification. Herein we demonstrate a flexible and rapid approach
to access a diverse chemical space that can be applied to a wide range
of natural product scaffolds.