OBJECTIVES

The objectives of this multidisciplinary project are

• To combine the knowledge in marine genomics with advanced methods in target-oriented drug screening and sustainable development for the discovery of novel natural products of biomedical / biotechnological interest from sponges, associated microorganisms and marine bacteria, living in temperate or in extreme marine environments.

• To use this knowledge for an efficient primary and secondary screening, including molecular-biology-based approaches, and identification of bioactive metabolites and peptides/proteins, which besides neuroprotective, antimicrobial, and anti-ageing activities will include hitherto neglected areas, such as anti-osteoporotic, anti-protozoan/anti-plasmodial, and innate-immune-response-modulating bioactivities. 

• To use advanced molecular biological and chemical techniques for the efficient isolation, structure elucidation and characterization of novel natural products, including secondary metabolites and bioactive peptides.

• To develop and to introduce methods for fast identification of known compounds (dereplication) and for identification and characterization of minute amounts of natural products predicted by genome mining.

• To identify, isolate and express new cDNAs (genetic “blueprints”) of commercial interest from sponge genomes, coding for enzymes/proteins involved in biosynthesis/biotransformation of bioactive molecules of therapeutical and/or biotechnical use (such as enzymes involved in carotenoid/retinoid biosynthetic pathways).

• To identify and characterize of cDNAs/proteins of commercial interest (such as light responsive cryptochromes, heat/cold shock proteins, and enzymes/proteins involved in accumulation of rare earth elements), isolated from extreme (darkness, high temperature, high pressure) aquatic environments, including deep-sea and cold-water sponges, psychrophilic and thermophilic (hydrothermal vent communities) bacteria, and bacteria involved in mineral deposition of deep-sea manganese nodules and seamount crusts.

• To prepare metagenomic DNA libraries to access the whole aquatic bacteria diversity for genome mining (in silico identification of novel enzymes or other bioproducts for biomedical application).

• To apply advanced metagenomic and biosynthetic prediction techniques to specifically target genes and compounds of biomedical interest for sustainable production in a heterologous cultivable host (special focus: trans-AT polyketide synthases and proteusin enzymes).

• To harness the natural biosynthetic machinery in a combined biotechnological and synthetic approach to generate natural product analogues for structure-activity relationship studies (precursor directed / combinatorial biosynthesis – mutasynthesis – modification of natural / unnatural products).

• To identify the three-dimensional structural features of the bioactive natural and unnatural compounds synthesized through molecular modeling studies.

• To develop, scale-up and optimize the productivity of systems and fermentation processes for the sustainable large-scale production of selected bioactive compounds.

• To undertake preclinical studies of selected potential drug leads identified in the course of the project.