Expediting Natural Product Discovery with Mass-Spectrometry based Metabolomic Analyses

Abstract

Natural products remain valuable sources for modern drug discovery, yet natural product discovery is hindered by poor production in lab cultivated organisms and/or poor observability from complex microbial extracts. We hypothesized that producing organisms use their natural products to respond to environmental cues from competing organisms, to nutrients and other physical factors, and when grown in isolation in the lab the organisms no longer receive these cues and subsequently do not produce their compounds of interest. Herein we describe the applications of environmental stimuli to boost natural product production in cave-derived actinomycetes in combination with comparative metabolomics analyses to prioritize natural products from whole culture extracts. In addition to prioritization with principal component analyses, we demonstrate for the first time the utility of self-organizing map analytics to prioritize natural products from large numbers of stimuli conditions within a single analysis. Many of the metabolites prioritized by comparative metabolomics were isolated and identified as natural products some of which, the ciromicins and funisamine, were identified as entirely novel natural products.