EVOBIOTIC: Capturing the natural antibiotic'ome: Developing Nature's EVOlved AntiBIOTIC

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Naturally evolved antibiotics are our primary mode of treating drug-resistant pathogens. Although
individual antibiotics do succumb to resistance via pressures they place on organisms, the
producers of these agents innovate through modular antibiotic drug (bio)synthesis programs to
naturally thwart drug resistance mechanisms. Moreover these same antibiotic drug biosynthesis
programs, are now revealed to construct other agents that perturb microbial physiology apart from
killing (i.e. blocking resistance). The evolutionary constraints that have produced these evolved
genetically encoded natural drugs are difficult to envision but their specificities, dynamic actions,
multi-pronged functions have clearly rendered them as privileged molecules. Much research has
defined the codes embedded within these natural small molecule biosynthesis programs and
surprisingly these codes and rules are largely followed across all known organisms that generate
polyketide and nonribosomal peptide molecules. In addition to the cracking of the nonribosomal
and polyketide codes, further facilitating their genomic-based identification is the clustering of
genes associated with the synthesis of a particular molecule-type (natural product/antibiotic) and a
collinear pattern used in their synthesis. Collectively, these natural principles and rules have now
created an exceptional opportunity to drive the detection and discovery of these molecules using a
genomic start point. New transformative approaches to antibiotic discovery are needed, and the
research in this proposal will lead to disruptive innovation, and a major departure in how historically
antibiotics have been found and investigated. With our unique approaches we will enrich in agents
with new modes of action, and those with a high likelihood of synergizing with clinically used
antibacterials. The following aims are designed to provide this forward-looking view of how to treat
antibiotic resistant bacteria:
AIM 1) Uncover the secondary metabolomes of antibiotic producers and define antibiotic
chemical-chemical interactions and synergy.
AIM 2) Interrogate the bioproduction of antibiotics from genomically identified unexplored
microbes using metabolomics
AIM 3) Test naturally evolved drugs against secretion systems and serum resistance systems of
gram negative/drug-resistant organisms