Probing the Structure−Function Relationship of Polyene Macrolides:  Engineered Biosynthesis of Soluble Nystatin Analogues

• Published in: Journal of medicinal chemistry 2006-04, Vol.49 (8), p.2431-2439
• Main Authors: Borgos, Sven E. F., Tsan, Pascale, Sletta, Håvard, Ellingsen, Trond E., Lancelin, Jean-Marc, Zotchev, Sergey B.
• Format: Article
• Language: English
• Subjects: Antibiotics; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological and medical sciences; Biotechnology; Fundamental and applied biological sciences. Psychology; Genetic Engineering; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Life Sciences; Macrolides - chemistry; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Multienzyme Complexes - chemistry; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Nystatin - analogs & derivatives; Nystatin - biosynthesis; Nystatin - chemistry; Polyenes - chemistry; Production of active biomolecules; Solubility; Streptomyces - enzymology; Streptomyces - growth & development; Streptomyces - metabolism; Streptomyces noursei; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050895w

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.