Antimicrobial natural products from Arctic and sub-Arcticmarine invertebrates

Abstract

Infectious diseases are a leading cause of death world-wide and there is a growing need for new anti-infective agents to combat multi-resistant strains of bacteria and fungi. Marine natural products are promising sources of novel antimicrobial compounds. In the present thesis, an investigation into the antimicrobial metabolites of Arctic and sub-Arctic marine invertebrate species is presented. Extracts of seven ascidian species, six sponge species, a soft-alcyonid coral and a bryozoan species, were screened for their antimicrobial activities. The extracts were pre-fractionated by solid phase extraction (SPE) and purified by reversephase high-performance liquid chromatography (RP-HPLC). Active metabolites were characterized by electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR) techniques. <br>The antibacterial tyrosine-derived guanidines, 3-dihydroxy-tubastrine and tubastrine, have been isolated from the ascidian Dendrodoa aggregata. This is the first report on the isolation of active metabolites from D. aggregata. 3-dihydroxy-tubastrine has previously been isolated from the Australian sponge species Spongosorites sp. The compound was present in high concentrations in extracts of the ascidian and could serve as a chemotaxonomic marker for the species. <br>Extracts of the ascidian Synoicum pulmonaria displayed the highest antimicrobial activities in our assays. Bio-guided fractionation of the extract, revealed the presence of three novel compounds, named synoxazolidinones A, B and C. The structures of the compounds were elucidated by spectroscopic methods including 1D and 2D NMR techniques, and analysis of mass spectrometric data. The absolute configuration of the compounds was also established by computational methods. The synoxazolidinones contain a unique 4-oxazolidinone core rarely encountered in natural products. Biogenetically, the compounds appear to be derived from arginine and tyrosine. This is the first report on the chemistry of S. pulmonaria. Synoxazolidinones also displayed anticancer activities and provide novel chemical scaffolds for structure-activity relationship studies which are currently being carried out. <br>The dibrominated tryptophan-derived metabolite, eusynstyelamide B, and three new derivatives, eusynstyelamides D, E and F, have been isolated from the bryozoan Tegella cf. spitzbergensis. The structures of the compounds were elucidated by mass spectrometry and, 1D and 2D NMR techniques. All four compounds displayed potent antibacterial activities in our assays. This is the first report of bioactive metabolites from T. spitzbergensis. Eusynstyelamide B has previously been isolated from the Australian ascidian Eusynstyela latericius. The presence of the same metabolites in different organisms and environments, suggests biosynthesis by symbiotic microorganisms. <br>In addition, this thesis provides background information on natural product research and current antimicrobial investigations of marine invertebrate species. The potential of Arctic and sub-Arctic marine invertebrates as sources of structurally novel, bioactive metabolites is demonstrated.