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Abstract
English abstract
The projects described in this dissertation are mainly focused on exploration of microorganisms as a source of interesting pharmacologically active natural products. The principal objective of this study has been directed to the isolation and structure elucidation of biologically active secondary metabolites from marine fungi and terrestrial bacteria.
The first project aimed to isolate fungi associated with the marine sponge Gellius bubastens collected from Suez Canal. Several fungal symbionts were identified by the use of DNA sequencing combined with World Wide Web (WWW) searchable databases. Bioassay guided fractionation of the extract of saline czapek’s dox yeast culture of marine-derived Aspergillus flavus led to the isolation of eight known compounds; kojic acid, aflatoxin B1, maculosin 1, hexahydro-3-(4-hydroxybenzyl)pyrrolo[1,2-a]pyrazine-1,4-dione, alpha-cyclopiazonic acid, cyclopiazonic acid imine, aspergillic acid and hydroxy aspergillic acid. Structure elucidation of isolated compounds was based on dereplication using one dimensional and/or two dimensional NMR and MS data. The lipid content of the crude extract of A. flavus was studied using GC/MS and led to the identification of more than fifty compounds with reported diverse bioactivities.
A cultivation-based approach was employed to compare the secondary metabolites diversity associated with A. flavus in eight different sea water culture media. The type of medium exhibited a significant difference of the yield and the type of compounds responsible for biological activities of the corresponding extract.
The antifungal activities exhibited by bacteria, such as Burkholderia have led to a strong interest in exploiting these properties as biological agents to control fungal infections. Bioassay guided purification of the active principles of Burkholderia ambifaria 2.2N using a panel of pathogenic fungi led to the discovery of a complex mixture of lipopeptides, the burkholdines. In this study we report the structure elucidation of the new and potent antifungal octapeptides; burkholdine 1229 (Bk-1229) and burkholdines 1097 (Bk-1097). Bk-1229 and Bk-1097 are octapeptides comprised of nonproteinogenic amino acids, including beta-hydroxytyrosine, beta-hydroxyasparagine, and a new fatty amino acid (FAA). Burkholines also are comprised of proteinogenic amino acids, two serine, two asparagines and glycine residues. Bk-1229 is a glycopeptide that contains a xylose moiety. Bk-1229 and Bk-1097 possess fungicidal against a panel of fungi with potencies 2-60-fold better than amphotericin B activity.
Key words: Burkholderia ambifaria, Aspergillus flavus, antifungal, cytotoxic, symbiosis, comparative study, lipopeptides.