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Date of Award

Fall 2012

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Supervisor

Justin Nodwell

Language

English

Abstract

Secondary metabolites are vital to human health and strategies to improve their production and detection are equally essential. The blue pigmented metabolite actinorhodin produced by Streptomyces coelicolor, a genus renowned for their diverse secondary metabolites, provides a unique opportunity to identify small molecules probes of secondary metabolism. Small molecules capable of altering secondary metabolism will have widespread application in the streptomycetes due to their ease of addition to any culture condition. Taking advantage of the phenotypic versatility of the S. coelicolor lifecycle, we extended our search for small molecule modulators further to include the entire developmental process. In addition to alterations in secondary metabolism, these processes include growth inhibition, precocious sporulation and alterations in aerial hyphae formation and sporulation. This work provides the foundation for studying Streptomyces by chemical manipulation. Those compounds which stimulate secondary metabolism were narrowed down to 19 ARCs (for antibiotic remodeling compounds). From these, a set of 4 structurally related molecules, the ARC2 series, was identified as weak inhibitors of fatty acid biosynthesis and most likely lead to alterations in secondary metabolism through shifting precursors from primary to secondary metabolism. Consistent with the conservation of fatty acid biosynthesis within bacteria, the effect of the ARC2 series extends in general to the actinomycetes. This provides a simple strategy to alter the secondary metabolic profiles of a diverse range of actinomycetes.

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