Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors

Natural
products and their semisynthetic derivatives are an important
source of drugs for the pharmaceutical industry. Bacteria are prolific
producers of natural products and encode a vast diversity of natural
product biosynthetic gene clusters. However, much of this diversity
is inaccessible to natural product discovery. Here, we use a combination
of phylogenomic analysis of the microviridin biosynthetic pathway
and chemo-enzymatic synthesis of bioinformatically predicted microviridins
to yield new protease inhibitors. Phylogenomic analysis demonstrated
that microviridin biosynthetic gene clusters occur across the bacterial
domain and encode three distinct subtypes of precursor peptides. Our
analysis shed light on the evolution of microviridin biosynthesis
and enabled prioritization of their chemo-enzymatic production. Targeted
one-pot synthesis of four microviridins encoded by the cyanobacterium Cyanothece sp. PCC 7822 identified a set of novel and potent
serine protease inhibitors, the most active of which had an IC50 value of 21.5 nM. This study advances the genome mining
techniques available for natural product discovery and obviates the
need to culture bacteria.