Blessie, E.J.2019-08-042019-08-042019-03http://ugspace.ug.edu.gh/handle/123456789/31937PhDDiscovery of new drugs have shifted from plants sources to microorganisms due to the enormous diversity of the latter. Marine endophytic fungi (MEF) is underexplored as compared to their terrestrial counterparts for the discovery of anti-infection drugs. This study set out to identify and develop novel antifungal compounds from marine endophytic fungi sources using yeast genomics guided approach. Six priority marine fungal endophytes were fermented and the secondary metabolites produced were extracted using ethyl acetate. Crude extracts and fractions from solvent-solvent fractionation and chromatography were tested against S. cerevisiae and C. albicans. Majority of the extracts showed satisfactory antifungal activity (zone of inhibition > 11 mm). Sequence analysis of the fungi ITS-rDNA revealed that the isolates belonged to three major genera; Aspergillus, Clonostachys and Meyerozyma. An investigation of the mechanism of action of the extracts from the 6 endophytes indicated that these extracts targeted protein synthesis, ergosterol biosynthesis and RNA translation. The study also confirmed that production of bioactive metabolites by marine fungal endophytes is time-dependent and favours shorter incubation of fungal fermentation cultures. In vitro interactions of phenotype modulating compounds with either standard antifungal drugs or fungal extracts resulted in novel synergistic interactions against Candida albicans and Saccharomyces cerevisiae. Structural elucidation of the compounds in the bioactive fractions using mass spectrometry (ms/ms) identified 22 novel chemical structures which is anticipated to exhibit antifungal activity. Three fractions from MEF 134; 134 FD K1V1 V1, 134 FD K1V5V3 and 134 FD K2V3V5 were active against S. cerevisiae but not the pathogenic C. albicans. This is an indication of an antitumor cytotoxic compound and not an antifungal. The cytotoxicity effect of the three compounds against HepG2 cells was tested in a dose dependent manner. It was demonstrated that several cancer, metabolism-related pathways and gene xx ontologies were regulated by the treatment with the 3 fractions from marine endophytic fungi. The data generated in this study highlights the opportunities of exploring fungal endophytes as useful sources of antifungal compounds for treatment of infections caused by pathogenic fungi.enNew Chemical CompoundsAntifungal ActivityMarine Endophytic Fungal SourcesThesis