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Combinatorial Biosynthesis of Industrial Glycopeptides: Technology, Optimization and Production

Final Report Summary - COMBIG-TOP (Combinatorial Biosynthesis of Industrial Glycopeptides: Technology, Optimization and Production)

The increasing frequency of nosocomial infections due to multiresistant bacterial pathogens exerts a significant toll in the industrialised world. There is an urgent need for novel and better antibiotics that can supplement the existing armamentarium against pathogens which is a major challenge for the well-being of EU citizens. The general aim of this project was to integrate industrial and academic laboratories in a combined research and development (R&D) effort directed at generating new drug candidates, and providing effective and general tools for faster development of current premarket drugs. This was achieved by focusing on a single class of antibiotics, the glycopeptides, and using molecular biological methods including combinatorial biosynthesis, a methodology to mix and match genes from different gene clusters in order to create novel "hybrid" products. This methodology can be used to replace complex chemical synthesis with direct fermentation processes.

Glycopeptides are an important class of antibiotics, interfering with the bacterial cell wall, with vancomycin and teicoplanin currently in clinical use. They are often "drugs of last resort" in treating life-threatening infections. On the other hand, the emergence of resistance to glycopeptides among Enterococci and Staphylococcus aureus has renewed interest in this class of antibiotics. Promising results were obtained with the development of semi-synthetic derivatives with improved activity, expanded antibacterial spectrum or better pharmacokinetics. Therefore, a significant potential existed to obtain improved glycopeptides by manipulation of these naturally occurring compounds.

However, glycopeptides are structurally complex molecules. The accessibility of analogues through chemical modification is thus limited to changes at only a few positions in the molecule. Combinatorial biosynthesis offers the unique opportunity of accessing the core of the glycopeptide molecule in a manner that is in principle scalable to industrial production.

One of the main issues in speeding up the development of a new drug is an efficient supply of compound by improvement of the producing strain, the fermentation process and/or the recovery of the active principle. For this reason, the physiology of the producing strain was investigated in detail. The availability of genomic data allowed comparisons with other actinomycetes, which in turn gave new insights into the requirements of an ideal host for glycopeptide production. Moreover, metabolic flux analysis is a very powerful tool for the overall objective to improve the productivity and characterise different production strains. Setting up and applying flux models combined with the knowledge on the biosynthesis pathway indeed resulted in mutants and protocols which significantly overproduce glycopeptides.

Special emphasis in the project was laid on the participation of small and medium-sized enterprises (SMEs). Two research-based companies were included to bring the obtained results to the market directly. One partner used the developed technologies for creating novel drugs by combinatorial approaches. Another's expertise in the rapid design of cell factories with enhanced metabolic function by flux analyses was incorporated in order to overcome the bottleneck in the development of new producing strains by metabolic engineering.