Improved Antifungal Polyene Macrolides via Engineering of the Nystatin Biosynthetic Genes in Streptomyces noursei
| Autor: | Olga Volokhan, Trond E. Ellingsen, Sergey B. Zotchev, Håvard Sletta, Alexander Dikiy, Ingrid Bakke, Olga N. Sekurova, Kristin F. Degnes, Ivan D. Treshalin, Aina Nedal, Elena P. Mirchink, Trygve Brautaset, Sven Even F. Borgos |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Nystatin MICROBIO Antifungal Agents Polymers Clinical Biochemistry Polyenes Biology Hemolysis Biochemistry Microbiology Mice Structure-Activity Relationship chemistry.chemical_compound Biosynthesis Polyol Candida albicans Drug Discovery medicine Animals Humans Molecular Biology Gene Pharmacology chemistry.chemical_classification Base Sequence General Medicine Polyene biology.organism_classification Streptomyces In vitro Acute toxicity CHEMBIO Streptomyces noursei chemistry Genes Bacterial Molecular Medicine Genetic Engineering medicine.drug |
| Zdroj: | Chemistry & Biology. 15:1198-1206 |
| ISSN: | 1074-5521 |
| Popis: | Summary Seven polyene macrolides with alterations in the polyol region and exocyclic carboxy group were obtained via genetic engineering of the nystatin biosynthesis genes in Streptomyces noursei . In vitro analyses of the compounds for antifungal and hemolytic activities indicated that combinations of several mutations caused additive improvements in their activity-toxicity properties. The two best analogs selected on the basis of in vitro data were tested for acute toxicity and antifungal activity in a mouse model. Both analogs were shown to be effective against disseminated candidosis, while being considerably less toxic than amphotericin B. To our knowledge, this is the first report on polyene macrolides with improved in vivo pharmacological properties obtained by genetic engineering. These results indicate that the engineered nystatin analogs can be further developed into antifungal drugs for human use. |
| Databáze: | OpenAIRE |
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