Increasing
evidence is accumulating that the origin of genetic regulation of many microbial
secondary metabolites can be traced to inter-kingdom and inter-generic interactions
within the native ecosystem of producing organisms. We ask the question: if
secondary metabolites are generally produced in response to external biochemical
and biological stimuli, can they be stimulated and revealed within a metabolome
by analyzing and organizing trends in the metabolite intensities across panels
of stimuli for a single organism grown in a single medium? Here we provide
data in support of the hypothesis that secondary metabolites are mediators of
stimuli response and we describe a system to organize the metabolomic
responses into maps that specifically reveal secondary metabolites. First, in a
model genomically characterized Streptomyces, we demonstrate how a significant
fraction of known secondary metabolism is stimulated and displayed via stimulus
mapping and how a large fraction of transcriptionally silent metabolism can be
activated and identified without genetic recombinant manipulation. Second, we
apply this method to the discovery of several new polyketides, including a
highly modified aromatic and a new macrolactam, from a genomically characterized
Nocardopsis species.