Extremely powerful analytical chemical and statistical techniques have arisen in recent years for leveraging metabolomic data for chemical biological discovery. As secondary metabolites are a meaningful and integral component of the complete metabolic inventory of microorganisms, we propose that contemporary metabolomics approaches can be successfully adapted to create new paradigms for accelerated antibiotic discovery and to provide methods for investigating microbiological basic science at the metabolome scale. In this presentation we first describe (1) a generalizable framework for secondary metabolic derepression and comparative metabolomic analysis for unbiased and sensitive detection and identification of new metabolites resulting from derepression. We discuss radically new methods for metabolomics analysis ideally suited to simultaneous analysis of hundreds of metabolomics datasets for secondary metabolite expression following derepression. (2) There is increasing evidence demonstrating that antibiotic resistance mutations and antibiosis mechanisms leave a detectable imprint on the microbial metabolome. Recent work from our lab demonstrates a strong link between vertically acquired antibiotic resistance and secondary metabolic gene expression. Further, as the end product of the central dogma, metabolomes can potentially encode how a microbe deals with antibiotic challenge. We hypothesize that the metabolic inventories of organisms exposed to lethal concentrations of antibiotics encode information pertaining to antibiotic mechanism, and we present data supporting this hypothesis. (3) Finally, we present a new technology that can potentially simultaneously discover new antibiotics and their mode of action transcending need for HPLC/MS and/or microtitre plates.
