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Discovery of Secondary Metabolites from Phenotypic Screens
thesisposted on 01.12.2019, 00:00 by Vanessa M Nepomuceno
Historically, microbially derived secondary metabolites have been strong contributors to biomedical research and human disease treatment. In particular, actinomycetes have had substantial impact as prolific producers of secondary metabolites with therapeutic significance. Herein, we postulate that actinomycete derived secondary metabolites harbor unique biological activity and structural novelty. To assess this, a library of actinomycete derived secondary metabolite fractions were subjected to variety of phenotypic screens. In addition, the potential of new versus standard screens to discover new structures was explored. Standard NP approaches were employed to isolate and structurally characterize two structurally novel SM were discovered from a marine derived Streptomyces sp. The first metabolite, N-acetyl-MY336-a, exists as amide rotamers and heterocyclic conformers. The second metabolite, 8β,17-epoxy-7β-hydroxy-12E,14-labdadiene, belongs to a large, common SM class of compounds, the diterpenoids. Additionally, a novel screen identified a Streptomyces secondary metabolite that functions as a QS inhibitor in GAS. To the best of our knowledge, the SM is the first of its kind as an inhibitor of GAS Rgg-mediated signaling. Moreover, molecular biology-based approaches determined that its putative target was determined to be the oligopeptide permease Opp. These studies illustrate the chemical and biological potential of secondary metabolites that can be identified through varied screening approaches.