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

EC contribution: : € 1.999.800
Duration: : 36 months
Starting date: : 01/01/2004
Funding scheme: : Specific Targeted Research Project
Keywords: : antibiotics, nosocomial infections, novel glycopeptides
Contract/Grant agreement number: : LSH- 503491
Project web-site: : http://www.combigtop.uni-tuebingen.de/

Background:

The focus of this proposal is on glycopeptides, a class of antibiotics where room for improvement is anticipated. The objectives are directed at generating new and more effective glycopeptide antibiotics by using combinatorial biosynthesis and at speeding up the development of new candidates by combining post-genomics techniques with modern molecular biotechnology and high quality academic research tightly interconnected with industrial research and production processes by two participating SMEs.

Problem:

Due to the rapidly increasing frequency of nosocomial infections caused by multi-resistant bacterial pathogens there is an urgent need for novel and better antibiotics that can supplement the existing armamentarium against pathogens.

Aim:

The aim of this project is the generation of more effective glycopeptides by combinatorial biosynthesis and speeding up the development of promising glycopeptides through improvement of the fermentation process

Expected and obtained results:

Using either chemical methods or molecular genetic approaches we generated novel peptide backbones. Further on we elucidated the glycopeptide synthesis focusing on the synthesis of balhimycin by Amycolatopsis balhimycina. In addition, genes involved in glycopeptide tailoring reactions such as glycosyl transfer or halogenation, have been collected from different glycopeptide producers or identified by genetic screening. Combination of this knowledge led the development of novel glycopeptides with altered backbones, novel glycosylation patterns and other structural modifications. These drug candidates will be tested for their effectiveness as antibiotics.

To bring forward drug candidates we used 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 the glycopeptide production could be identified and eliminated, allowing the construction of an improved production strain, usable also for the novel glycopeptides generated by the project.

Potential applications:

New antibiotics for human health.

Coordinator:

Prof. Dr Wolfgang Wohlleben
University of Tübingen
Institute of Microbiology
Department of Microbiology/Biotechnology
Auf der Morgenstelle 28
72076 Tübingen, Germany
Tel. +49 070712976944
Fax +49 07071295679
wolfgang.wohlleben@biotech.uni-tuebingen.de

European Commission