Multifaceted approaches for accessing low-abundance microbial secondary metabolites

With recent advances in chromatographic, spectroscopic and computational techniques, it is now possible to elucidate the structures of complex natural products on vanishingly small quantities of material. Low-abundance metabolites that were previously dismissed as being “in the grass” are now comfortably within the reach of most modern biodiscovery platforms.

Unsurprisingly, this has led to an explosion in the number of structures reported in the past decade, with the Dictionary of Natural Products now containing a staggering 300,000 entries. While each of these metabolites represents a remarkable technological and intellectual tour de force, the majority have been isolated in quantities that are only sufficient for a handful of rudimentary bioassays and virtually none are available for other researchers to access. In the absence of a facile synthetic route, these precious molecules will invariably end up as little more than intellectual curiosities in the scientific literature.
To address this challenge, we have recently completed a three-year campaign to isolate 5,000 metabolites from a unique collection of Australian microorganisms. While structural novelty of the isolated metabolites was an important consideration, the primary objective of the project was to isolate both novel and previously reported metabolites in quantities sufficient for comprehensive biological evaluation, both in-house and by other researchers with unique bioassays. To meet our ambitious targets, we employed a range of “top-down” and “bottom-up” approaches, including cultivation on exotic growth media, addition of exogenous stimulators/epigenetic modifiers, cocultivation, genome mining, addition of transcriptional activators and biosynthetic pathway reconstruction in heterologous hosts.

This presentation will highlight selected case studies from our journey that exemplify our highly collaborative and multidisciplinary approach to microbial biodiscovery.