Diminishing resources of terrestrial sourced compounds and the redundancy of synthetic chemistry based drugs has driven natural product research to probe the depths of the oceans for new secondary metabolites. In a project led by the University of Strathclyde in conjunction with the EU funded project Seabiotech, a metabolomic-based approach to drug discovery was utilised, to analyse and scale up the production of bioactive metabolites from marine microorganisms, using a cocultivation technique. Initially, a small scale study investigated three different strains of Streptomyces isolated from marine sediments near Oban, co-cultured with Rhodococcus sp. (SBT017) extracted from the sponge Sycon ciliatum, to increase the yield of novel secondary metabolites attained. SBT1625 (Streptomyces somaliensis) and SBT681 (Streptomyces sp.) cocultures were selected to scale-up the production of bioactive secondary metabolites for the treatment of metabolic diseases. Mass spectroscopy (MS) and 1D & 2D nuclear magnetic resonance (NMR) spectroscopy experiments in parallel with computer based metabolomic tools were adopted to chemically investigate the crude extracts, fractions and sub-fractions for bioactive metabolites with activity against the disease biomarkers; HDAC6, EL and PPARα. A total of 14 metabolites were isolated and structures were elucidated, seven of which are new metabolites not previously described, with six from bioactive fractions. A notable discovery was that of a novel proline-rich peptide SBT681/SBT017 co-culture that had exemplary inhibitory action (103.42%) for EL. Similarly, a fatty acid derivative isolated from the same co-culture had good bioactivity against a number of disease markers; principally the inhibition of HDAC6 (78.63%), but also of PPARα & PPARδ (36.49%). SBT1625/SBT017 co-culture also demonstrated the benefit of utilising cocultivation as a means to increase metabolite yields obtained. Marine derived natural product research offers an exciting and vastly untapped resource of novel secondary metabolites for the drug discovery pipeline.
|Date of Award||28 Apr 2017|
- University Of Strathclyde
|Sponsors||EPSRC (Engineering and Physical Sciences Research Council) & University of Strathclyde|