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Combinatorial biosynthesis: generation of novel therapeutic substances by combining genes from actinomycetes and cyanobacteria

   
Project

QLK3-2000-00131

Cell factory area

3.1.2

EU Contribution

1 712 899 Euro

Duration

36 months

Type

Research project

Starting date

01-01-2001

Keywords
actinomycetes
combinatorial diosynthesis
cyanobacteria
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ABSTRACT
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The research aims to find novel therapeutic substances. This will be achieved by:

  • Screening of bacteria, actinomycetes and cyanobacteria with modern fingerprinting techniques and by
  • Combinatorial biosynthesis. The latter approach includes the creation of expression systems for genes derived from cyanobacteria.

The compounds obtained from wild type bacteria and those derived from genetically engineered strains are screened through antimicrobial, antitumour and receptor-based systems. Biopharmaceutical evaluation of the hits that will be found in the project leads to optimisation of the promising target molecule in the early phase of drug development process. Seven European groups, four academic and three SMEs form the multidisciplinary project team.

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OBJECTIVES
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The major aim of the project is to find a novel lead molecule for drug development. To achieve the goal, two strategies are used:

  • Screening of 600 bacteria by fingerprinting to obtain novel natural products.
  • Combinatorial biosynthesis (combination of biosynthetic routes of metabolites by gene technology).

Therefore, the other objectives are:

  • A screening model for natural products.
  • Cloning of eight different biosynthetic gene clusters representing three different metabolite classes.
  • Combining genes in cassettes already available to join the chemical patterns of three distinct metabolites.
  • Expressing the biosynthetic genes derived from cyanobacteria in streptomycetes.
  • Determining the chemical structures and bioactivities of compounds.
  • Biopharmaceutical evaluation of promising molecules.

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DESCRIPTION OF THE WORK
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Seven partners, four academic groups and three SMEs form a multidisciplinary team to carry out the proposed project. The final aim of the proposal is a novel lead molecule for drug development. The project focuses on products of two bacteria, actinomycetes and cyanobacteria, that are known producers of secondary metabolites with important bioactivities. Academic groups have expertise on molecular biology and chemistry, whereas SMEs are mainly committed to bioactivity screens. Six hundred bacterial strains will be analysed using genetic and chemical fingerprinting techniques.

Based on the bioinformatics obtained, the bacterial strains producing distinct metabolite patterns will be selected for further studies:

  • The extracts of these strains for bioactivity screens (antimicrobial, antitumour and receptor-based assays).
  • The genetic material for combinatorial biosynthesis.

Based on the bioactivity data, the metabolites of selected strains will be isolated. Chemical nature of novel molecules is determined by spectroscopy. Molecular biology groups use gene cassettes already available in their laboratories and they start combinatorial biosynthesis using genes already cloned. Random and desired gene combinations generate bacterial strains producing extraordinary molecular structures. Combinatorial biosynthesis in the proposed project is focused on combining building blocks derived from different compound classes thus creating a model to produce compound libraries of high diversity. Chemical and bioactivity nature of each compound generated by combinatorial biosynthesis will be analysed. As soon as the first promising compounds are available, biopharmaceutical evaluation will take place to direct the further modification of the target molecule. Modification will be achieved by gene technology.

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DELIVERABLES
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Deliverables of the project are meeting reports and technical implementation plans. Screening strategy obtained by DNA and chemical fingerprinting of secondary metabolites will be published. As 600 bacteria will be characterised for screening purposes, the well-characterised bacterial strains are considered as deliverables in the consortium. During the project several cloned and identified genes for bioactive metabolites will be delivered in the consortium together with expression casettes for generation and modification of lead compounds. Most important deliverables are bioactive molecules either natural or seminatural origin for further development to drug candidates.

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CONSORTIUM
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COORDINATOR
  Kristiina Ylihonko
Galilaeus Oy
20781 Kaarina, Finland
Tel: +35 822741450
Fax: +35 822731460
kristiina.ylihonko@galilaeus.fi

PARTNERS
  Thomas Börner
Department of Genetics
University of Humboldt
Institute of Biology
10115 Berlin, Germany
Tel: +49 3020938142
Fax: +49 3020938141
thomas.boerner@biologie.hu-berlin.de

Pekka Mäntsälä
Department of Biochemistry
University of Turku
20014 Turku, Finland
Tel: +35 823336850
Fax: +35 823336860
pekka.mantsala@utu.fi

Hans von Döhren
Max-Volmer Institute
Technical University of Berlin
10857 Berlin, Germany
Tel: +49 3031422697
Fax: +49 3031424783
doehren@chem.tu-berlin.de

Francisco Malpartida
Centro Nacional de Biotechnologia
Campus Universidad Autonoma de Madrid
28049 Madrid, Spain
Tel: +34 915854548
Fax: +34 915854506
fmalpart@cnb.uam.es

Juha-Matti Savola
Juvantia Pharma Ltd
20520 Turku, Finland
Tel: +35 823337684
Fax: +35 823337680
juha-matti.savola@juvantia.com

Sveinbjorn Gizurarson
Lyfjathroun Hf
101 Reykjavik, Iceland
Tel: +35 45112020
Fax: +35 45112021
sg@lyf.is
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