Lessons learned from the transformation of natural product discovery to a genome-driven endeavor

Abstract

Natural product discovery is currently undergoing a transformation from a phenotype-driven field to a genotype-driven one. The increasing availability of genome sequences, coupled with improved techniques for identifying biosynthetic gene clusters, has revealed that secondary metabolomes are strikingly vaster than previously thought. New approaches to correlate biosynthetic gene clusters with the compounds they produce have facilitated the production and isolation of a rapidly growing collection of what we refer to as “reverse-discovered” natural products, in analogy to reverse genetics. In this review, we present an extensive list of reverse-discovered natural products and discuss seven important lessons for natural product discovery by genome-guided methods: structure prediction, accurate annotation, continued study of model organisms, avoiding genome size bias, genetic manipulation, heterologous expression, and potential engineering of natural product analogs.

Characterization of caulonodin lasso peptides revealed unprecedented N-terminal residues and a precursor motif essential for peptide maturation

“…Only unambiguous coupling constants were used. Thus, 3 J HNa $ 9 Hz was observed for Ser1, Ile2, Asp4, Gly6, Thr15 and Tyr16. The torsion angles f of these residues were restrained to À120 AE 30 .…”

“…1,2 While selective screenings for certain bioactivities have been performed in the past by bacterial or fungal fermentations, nowadays the rational approaches gain more ground. 3,4 In particular, genome mining driven predictions and isolations of new compound become more common 5,6 as sequencing costs drop dramatically. Thousands of bacterial genomes have been already sequenced, providing large amounts of data to be analyzed in upcoming research.…”

Microbial genome mining for accelerated natural products discovery: is a renaissance in the making?

“…If we look beyond NRPS and type I PKS pathways, which require substantial coding capacity, it is becoming apparent from recent genome mining successes that many microbes with smaller genomes encode ribosomally synthesized and post-translationally modified peptides (RiPPs) or phosphonates [24, 44, 52]. Perhaps these discoveries will contribute to a more robust drug discovery process in coming years.…”

Biodiversity of genes encoding anti-microbial traits within plant associated microbes

“…The revolution in genomics, genome mining tools and bioinformatics offers a new opportunity to connect biochemical diversity to the underlying genetic diversity and to analyze the evolutionary events leading to biodiversity (Zotchev et al, 2012 ; Scheffler et al, 2013 ; Deane and Mitchell, 2014 ).…”