The focus of this proposal is on glycopeptides, a class of antibiotics where room for improvement is anticipated and the second-generation glycopeptide dalbavancin is under development by one SME of this team. The objectives of this proposal are directed at generating more effective glycopeptides by combinatorial biosynthesis and at speeding up the development of promising glycopeptides through improvement of the fermentation process. The project will start with the generation of novel peptide backbones, either chemically or by exchanging gene fragments determining amino acid specificity. Genes involved in subsequent tailoring reactions, such as the coupling reactions, glycosyl transfer, halogenation, and the supply of activated sugars or amino acid precursors will be collected from glycopeptide producers or identified by genetic screening. Knowledge of the enzymatic reactions will enable gene combinations to generate novel glycopeptides with altered backbones, novel glycosylation patterns, and other modifications. These compounds will be tested for their effectiveness as antibiotics. To bring forward drug candidates, we will combine post-genomics techniques (proteome/transcriptome) with modern molecular biotechnology to optimise the production process. This will be achieved by flux analyses and 2D-maps for discovering primary metabolism proteins up-regulated during glycopeptide production. Combined with a study of other limiting steps, such as precursor uptake and product excretion, and with transcriptional regulation of glycopeptide genes, bottlenecks in production will be identified and eliminated, allowing the construction of an improved production strain, usable also for the novel glycopeptides generated by the project. By combining combinatorial biosynthesis integrated with modern molecular techniques, high quality academic research becomes tightly interconnected with industrial research and production processes by the two participating SMEs.
|Period||01/01/2004 → 31/12/2006|
|Financing source||Forsk. EU - Rammeprogram|
|Research programme||Forsk. EU - Rammeprogram|
|Amount||2,400,000.00 Danish Kroner|