Since the discovery of penicillin, fungi have been in the spotlight as a prolific source of bioactive agents with many examples in the literature emphasising their importance in drug discovery. In our efforts towards the discovery of new bioactive fungal metabolites from niche ecosystems, several fungal strains were isolated from marine organisms and plants collected from Hurghada (Red Sea) and Wadi El Natrun valley, respectively. Based on the antimicrobial screening against a panel of pathogenic microorganisms, fifteen endophytic or invertebrate-associated fungal isolates were prioritised for further analysis. Chemical investigation was carried out for organic extracts obtained from small-scale fermentations. Specifically, analysis of the MS2 data through the GNPS platform revealed several known compounds which clustered with unidentified parent ions, suggesting the presence of new secondary metabolites. Fungal fermentation on rice afforded sufficient biomass for fractionation and separation which led to the isolation of a suite of new and known compounds belonging to various classes. In particular, itaconic acid and kojic acid derivatives were isolated from a Cladosporium sp., whereas a new cyclo-peptide and a new morpholine-2,5-dione were isolated from an Epicoccum sp. and Alternaria sp., respectively. Moreover, potentially new analogues of emericellamide A were identified in the molecular network of the crude extract of a marine Aspergillus sp. An addtional Aspergillus strain produced a suite of butyrolactone derivatives. The pure metabolites were screened for antibiotic and cytotoxic activity. The ultimate goal of this interdisciplinary project is to incorporate the new antimicrobial compounds onto textile substrates to enhance their functionality.