Comparative Actinomycete genome analyses to support drug discovery
Author: Candace Farmer
Drugs from natural, evolved sources remain uniquely attractive for solving therapeutic problems with no current relief. For example, see in this recent PNAS article how the Principal Investigator and his former pharmaceutical team used massive genome mining to uncover a natural novel drug-like molecule produced by bacteria that is now predicted to disrupt a key COVID-19 infection pathway:
Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface
For this project, three sets of samples were reviewed. The first set of 96 samples were sequenced and data were assembled for review. The second set of 15 samples with existing libraries were sequenced on MiSeq600. The final set of 10 was sequenced on the PacBio.
Most of the sequenced strains still require comprehensive analysis. However, Dr. Blodgett’s team is currently drafting three publications that require sequence information derived from this project. A-A Microbial Resource Announcement comparing the genome sequences of the related environmental PTM-producing actinomycetes CM02 and JV180.This publication will then act as a foundation for comparing PTM-associated promoter structures across a much larger panel of related Streptomyces strains. B-A global comparison of all known PTM cluster types, that includes two completely novel cluster types revealed by genome sequencing in this project from local St Louis isolates (CS02 and BM10)C-A collaborative genomic discovery paper to describe the chemical structure of a new piperazyl molecule produced by newly sequenced strain BE230.
Dr. Blodgett anticipates this wealth of new genome sequence data will serve the lab as a resource to guide the discovery of new medicinal-like compounds for the next 5-10 years, not to mention provide incredible necessary source material for parallel genetic, biosynthetic and regulatory inquiries. These types of studies are the sharp end of the discovery path for modern natural product drug discovery and lead scaling, providing critical insights on how to leverage nature(microbes)for unmet clinical need.
Read the newest paper: https://www.pnas.org/content/118/31/e2103515118