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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Biopolymers
Bioprospecting
of marine microorganisms
Biosyntesis
of L-Lysin from Methanol
Gene
Expression
Osmoregulation
Metabolic
Engineering