Drug discovery from marine microbes A chemical evaluation of Hawaiian marine microbial biodiversity and its potential towards the discovery of novel antibiotic and anticancer pharmaceuticals

Studies directed towards the discovery of pharmaceutical lead compounds for the treatment of neoplastic and infective diseases from marine microorganisms of the Hawaiian archipelago have led to the isolation of 42 bioactive compounds, 35 of which were derived from marine bacteria, 6 from marine fungi and 1 from a sponge. The elucidation of their chemical structures using modern analytical methods resulted in the identification of 10 new secondary metabolites with pharmaceutical potential. Within the scope of this work, the most prolific strains in terms of the production of novel secondary metabolites were shown to belong to the genus Pseudoalteromonas : Two red-pigmented marine bacteria designated CMMED418 and CMMED294 were identified as previously undescribed Pseudoalteromonas spp. on the basis of 16S rRNA and gyrB gene sequences. The strains produced a new class of prodigiosins with a hitherto unprecedented substitution at C-2, supporting studies that have demonstrated the multifaceted biosynthesis of prodiginine-type secondary metabolites in various microbial organisms. The major metabolite, 2-(p-hydroxybenzyl)-prodigiosin, was active against human ovarian adenocarcinoma cells and inhibited human topoisomerase I. The structure of 2-(p-hydroxybenzyl)-prodigiosin was elucidated on the basis of homo- and hetero-correlated NMR experiments; the minor metabolites were characterized on the basis of their collision-induced fragmentation patterns using tandem mass spectrometry. Two additional Pseudoalteromonas spp., CMMED290 and CMMED291, produced 2,3,5,7-tetrabromobenzofuro[3,2-b]pyrrole, a highly brominated anti-MRSA antibiotic with a new tricyclic benzofuropyrrole core structure that is unprecedented amongst natural products. Structure elucidation was facilitated by computational methods. The IC50-value of the compound against the clinical target MRSA was evaluated and compared to other highly brominated metabolites. Lastly, the unusual production of indolmycin by the Gammaproteobacteria CMMED301 and CMMED769 prompted closer investigation of their phylogenetic origin and resulted in the chemical and biological description of the novel bacterial species Pseudoalteromonas hawaiiensis. Methods for the delineation from the seemingly closely related species Pseudoalteromonas luteoviolacea are described.;In addition, further marine isolates that have yielded interesting results in the course of the analysis of their pharmaceutical potential are discussed (Table 1). These include a bioactive dioxoenoic acid, isolated from the undescribed marine bacterium CMMED169; a new nitrobenzoyl sesquiterpenoid from the marine fungus Aspergillus elegans CMMED235; the results of a large scale elicitation response experiment on marine fungi (Fusarium sp. LM252); bioactive compounds from the cyanobacterium Synechococcus sp. CMMED348; and a novel halichondramide A analog from the deep sea Pachastrissa sp. PS358.