title: Improved antifungal polyene macrolides via engineering of the nystatin biosynthetic genes in Streptomyces noursei.
abstract: 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.
authors.affiliation: Department of Biotechnology, SINTEF Materials and Chemistry, N-7034 Trondheim, Norway.
authors.forename: Trygve
authors.initials: T
authors.lastname: Brautaset
authors.forename: Håvard
authors.initials: H
authors.lastname: Sletta
authors.forename: Aina
authors.initials: A
authors.lastname: Nedal
authors.forename: Sven Even F
authors.initials: SE
authors.lastname: Borgos
authors.forename: Kristin F
authors.initials: KF
authors.lastname: Degnes
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bakke
authors.forename: Olga
authors.initials: O
authors.lastname: Volokhan
authors.forename: Olga N
authors.initials: ON
authors.lastname: Sekurova
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Treshalin
authors.forename: Elena P
authors.initials: EP
authors.lastname: Mirchink
authors.forename: Alexander
authors.initials: A
authors.lastname: Dikiy
authors.forename: Trond E
authors.initials: TE
authors.lastname: Ellingsen
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Zotchev
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D001483:Base Sequence; D002176:Candida albicans / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D005818:Genetic Engineering / Q000379:methods*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009761:Nystatin / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011090:Polyenes / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D011090:Polyenes; D011108:Polymers; C511411:S44HP; C024617:polyol; D009761:Nystatin