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Combinatorial biosynthesis for new drug discovery.

C R Hutchinson1

  • 1School of Pharmacy, Department of Bacteriology, University of Wisconsin, Madison WI, 53706, USA. crhutchi@facstaff.wisc.edu

Current Opinion in Microbiology
|March 6, 1999
PubMed
Summary

Combinatorial biosynthesis creates novel compounds by swapping genes in antibiotic-producing microbes. This genetic engineering approach, particularly with polyketide synthase (PKS) genes, enables the discovery of valuable new drugs.

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Area of Science:

  • Microbial genetics and metabolic engineering
  • Natural product drug discovery

Background:

  • Combinatorial biosynthesis allows the creation of novel metabolites by reconfiguring secondary metabolism gene clusters.
  • This strategy involves interchanging genes between microorganisms to form unnatural gene combinations or hybrid genes.

Purpose of the Study:

  • To explore the potential of combinatorial biosynthesis for generating new microbial metabolites and discovering valuable drugs.
  • To highlight the successful application of this method with polyketide synthase (PKS) genes and deoxysugar biosynthesis genes.

Main Methods:

  • Interchanging secondary metabolism genes between antibiotic-producing microorganisms.
  • Creating unnatural gene combinations or hybrid genes.
  • Extending the approach to include deoxysugar biosynthesis genes.

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Main Results:

  • Novel metabolites are produced due to new enzyme effects on metabolic pathways or altered protein properties.
  • Successful application with polyketide synthase (PKS) genes has yielded derivatives of macrolide antibiotics and polycyclic aromatic compounds.
  • Inclusion of deoxysugar biosynthesis genes further expands the scope for generating diverse microbial metabolites.

Conclusions:

  • Combinatorial biosynthesis is a powerful strategy for generating molecular diversity and discovering new drugs.
  • Genetic engineering of bacteria, particularly through PKS and deoxysugar gene manipulation, offers significant potential for pharmaceutical development.