COMBIG-TOP: Combinatorial biosynthesis of industrial glycopeptides: technology, optimization and production

• Research unit: EU RFP
• Project number: 03.0080

Key words (English)

Antibiotic; vancomycin; glycopeptide; biosythesis

Alternative project number (English)

EU project number: 503491

Research programs (English)

EU-programme: 6. Frame Research Programme - 1.1.1b

Short description (English)

See abstract

Abstract (English)

There is a need to discover more effective antibiotics to combat multi-resistant bacterial infections and to speed the development of new products. The focus of this proposal is on glycopeptides, since they represent one class of antibiotics where room for improvement is anticipated. The objectives here are to develop the interdisciplinary technology of combinatorial biosynthesis, apply it to the generation of novel glycopeptides, and to speed the development of promising new glycopeptides by optimization of the fermentation process. All aspects of glycopeptide biosynthesis will be investigated, including; the generation of novel peptide backbones using engineered non-ribosomal peptide synthetases; the subsequent tailoring enzymes such as the P450 monooxygenases involved in phenol couplings, glycosyl transferases, halogenases, and acylases; and the metabolic supply of activated sugars and amino acid precursors for glycopeptide biosynthesis. Libraries of glycopeptide biosynthetic genes will be collected from glycopeptide producers or identified by genetic screening. These genes will be re-combined to generate hybrid pathways for novel glycopeptides with altered backbones, novel glycosylation patterns, or modified acylation and halogenation patterns. To develop drug candidates, we will combine genomics-based research on the biosynthesis with modem molecular biotechnology, exploiting post-genomics techniques (proteome/transcriptome) to optimise an industrially viable production process. This will include flux analyses combined with 2D-gel analyses to identify proteins of primary metabolism up-regulated during the production of glycopeptides. The uptake of precursors and the excretion of product will also be studied. Finally, the transcriptional regulation of glycopeptide biosynthesis genes will be studied, to identify and eliminate bottlenecks in the production process.

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 03.0080