Microbially Guided Discovery and Biosynthesis of Biologically Active Natural Products

The design of small molecules that
inhibit disease-relevant proteins
represents a longstanding challenge of medicinal chemistry. Here,
we describe an approach for encoding this challengethe inhibition
of a human drug targetinto a microbial host and using it to
guide the discovery and biosynthesis of targeted, biologically active
natural products. This approach identified two previously unknown
terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an
elusive therapeutic target for the treatment of diabetes and cancer.
Both inhibitors appear to target an allosteric site, which confers
selectivity, and can inhibit PTP1B in living cells. A screen of 24
uncharacterized terpene synthases from a pool of 4464 genes uncovered
additional hits, demonstrating a scalable discovery approach, and
the incorporation of different PTPs into the microbial host yielded
alternative PTP-specific detection systems. Findings illustrate the
potential for using microbes to discover and build natural products
that exhibit precisely defined biochemical activities yet possess
unanticipated structures and/or binding sites.