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last update: September 26, 2007

Engineered antibiotic synthesis

Antibiotics represent a group of the industrially important compounds used for the treatment of human and animal infectious diseases. With the rapid evolution of the multi-resistant pathogens the need for new antibiotics is growing. Among the several thousand of different antibiotics discovered so far, more than two thirds are produced by bacteria. With today's knowledge of the genetics and biochemistry of the bacterial antibiotic synthesis it becomes possible to make new antibiotics with improved properties via genetic engineering of the producing organisms. We are studying antibiotic biosynthesis and its regulation in Streptomyces bacteria, both for the purpose of improving the production levels and with the aim of creating new antibiotics. In particular, we are taking advantage of the nystatin biosynthetic genes, which we have recently cloned from the Gram-positive bacterium Streptomyces noursei . Our goal is to study the process of nystatin biosynthesis in this bacterium, and to create new antifungal antibiotics.

Based on the research on engineered antibiotic biosynthesis, a biotech company Biosergen AS has been established in 2004. The company is engaged in development of novel antifungals through genetic engineering of the nystatin biosynthetic genes combined with chemical modifications.

In addition, we are working on engineered biosynthesis of other antibiotics discovered in the bioprospecting project.

Key Papers:
Volokhan, O., Sletta, H., Ellingsen, T.E., Zotchev, S.B. (2006). Analysis of the P450 monooxygenase NysL responsible for the C10 hydroxylation during the biosynthesis of polyene macrolide antibiotic nystatin in Streptomyces noursei. Appl Environ Microbiol 72:2514-2519.

Zotchev, S.B., Stepanchikova, A.V., Sergeiko, A.P., Sobolev, B.N., Filimonov D.A., Poroikov V.V. (2006). Rational design of macrolides by virtual screening of combinatorial libraries generated through in silico manipulation of polyketide synthases. J Med Chem 49:2077-2087.

Borgos, S.E.F., Tsan, P., Sletta, H., Ellingsen, T.E., Lancelin, J.-M., Zotchev, S.B. (2006). Probing the structure-function relationship of polyene macrolides: soluble nystatin analogues produced via manipulation of the nystatin polyketide synthase. J Med Chem 49:2431-2439.

Sletta, H., Borgos, S.E.F., Bruheim, P., Sekurova, O.N., Grasdalen, H., Ellingsen, T.E., Zotchev, S.B. (2005). Nystatin biosynthesis and transport: the nysH and nysG genes encoding a putative ABC transporter system in Streptomyces noursei ATCC 11455 are required for efficient conversion of 10-deoxynystatin to nystatin. Antimicrob Agents Chemother 49: 4776-4583.

Fjærvik, E., Zotchev S.B. (2005). Biosynthesis of the polyene macrolide antibiotic nystatin in Streptomyces noursei. Appl Microbiol Bitechnol 67: 436-443.

Bruheim, P., Borgos, S.E.F., Tsan, P., Sletta, H., Ellingsen, T.E., Lancelin, J.-M., Zotchev, S.B. (2004). Chemical diversity of polyene macrolides produced by Streptomyces noursei ATCC 11455 and recombinant strain ERD44 with genetically altered polyketide synthase NysC. Antimicrob Agents Chemother 48: 4120-4129.

Sekurova, O.N., Brautaset, T., Sletta, H. Borgos, S.E.F., Jakobsen, Ø.M., Ellingsen, T.E., Strøm, A.R., Valla, S., Zotchev, S.B. (2004). In vivo analysis of the regulatory genes in the nystatin biosynthetic gene cluster of Streptomyces noursei ATCC 11455 reveals their differential control over antibiotic biosynthesis. J. Bacteriol 186:1345-1354.

Brautaset, T., Borgos S.E.F., Sletta, H., Ellingsen, T., Zotchev, S.B. (2003). Site-specific mutagenesis and domain substitutions in the loading module of the nystatin polyketide synthase, and their effects on nystatin biosynthesis in Streptomyces noursei. J Biol Chem 278: 14913-14919.

Brautaset, T., Bruheim, P., Sletta, H., Hagen, L., Ellingsen, T.E., Strøm, A.R., Valla, S., Zotchev, S.B. (2002). Hexaene derivatives of the polyene antifungal antibiotic nystatin produced as a result of an induced rearrangement within the nysC polyketide synthase gene in Streptomyces noursei ATCC 11455. Chem. Biol. 9:367-373.

Brautaset, T., Sekurova, O.N., Sletta, H., Ellingsen, T.E., Strøm, A., Valla, S., and S.B. Zotchev (2000). Biosynthesis of the antifungal antibiotic nystatin in Streptomyces noursei ATCC 11455: analysis of the gene cluster and deduction of the biosynthetic pathway. Chem. Biol., 7: 395-403.

Zotchev, S., Haugan, K., Sekurova, O., Sletta, H., Ellingsen, T.E., and Valla, S. (2000). Identification of a gene cluster for antibacterial polyketide-derived antibiotic biosynthesis in the nystatin producer Streptomyces noursei ATCC 11455. Microbiol. 146: 611-619.


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