Brian O. Bachmann, PhD
Professor of Chemistry
Department of Chemistry
Vanderbilt University, Nashville, TN
Host: Prof. Tim Bugni
Reconsidering the ‘Magic Bullet’ Approach to Drug Discovery
It is now possible to estimate the natural product biosynthetic potential of organisms before attempting to isolate compounds by analysis of their biosynthetic gene clusters. Moreover, a wealth of effective methods now exists to elicit biosynthetic gene cluster activation, a process collectively known as ‘genome mining’. However, isolating and structurally elucidating interesting encoded compounds continues to represent the major bottleneck in natural product discovery and we feel that a means of prioritization is needed that facilitates the determination of biological activity before attempting isolation. Herein we describe a method to assess the activity of metabolites produced via genome mining campaigns prior to their isolation. We describe an ultra-high throughput method to assess the activity of metabolites within a comprehensive metabolome in which we: (1) analyze the effects of metabolites against a heterogeneous biopsied mixture of diseased and healthy human cells (primary cells) derived from cancer patients, (2) across a broad panel of multiple cell status markers. We demonstrate the discovery and prioritization of aromatic and reduced polyketides against genotyped patient-derived primary cells, opening up an era of personalized natural product discovery.