title: Probing the structure-function relationship of polyene macrolides: engineered biosynthesis of soluble nystatin analogues.
abstract: Although polyene macrolides are efficient antifungal agents with fungicidal mode of action, their use in medical practice is problematic due to their low solubility and significant human toxicity. In an attempt to address the solubility problem, we have obtained two analogues of nystatin with hydroxy groups at positions C31 and C33 through manipulation of the nystatin polyketide synthase in the producing organism Streptomyces noursei. Structures of the analogues were confirmed by nuclear magnetic resonance (NMR), and their solubility was found to be more than 2000 times higher than that of nystatin. However, both analogues were shown to have lost antifungal activity, implying that the integrity of the hydrophobic polyene region of the nystatin molecule is crucial for the fungicidal action. NMR data and computer modeling performed for the new analogues suggested conformational changes together with a significantly increased structural disorder, which may account for both increased solubility and the loss of activity.
authors.affiliation: Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
authors.forename: Sven E F
authors.initials: SE
authors.lastname: Borgos
authors.forename: Pascale
authors.initials: P
authors.lastname: Tsan
authors.forename: Håvard
authors.initials: H
authors.lastname: Sletta
authors.forename: Trond E
authors.initials: TE
authors.lastname: Ellingsen
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lancelin
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Zotchev
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D005818:Genetic Engineering; D018942:Macrolides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009761:Nystatin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry*; D011090:Polyenes / Q000737:chemistry*; D012995:Solubility; D013302:Streptomyces / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D018942:Macrolides; D009097:Multienzyme Complexes; D011090:Polyenes; D009761:Nystatin