Borgos Sven E F, Tsan Pascale, Sletta Håvard, Ellingsen Trond E, Lancelin Jean-Marc, Zotchev Sergey B
Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
J Med Chem. 2006 Apr 20;49(8):2431-9. 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.
尽管多烯大环内酯类是具有杀菌作用模式的高效抗真菌剂，但由于其低溶解度和对人体的显著毒性，它们在医学实践中的应用存在问题。为了解决溶解度问题，我们通过对产抗生素的诺尔斯链霉菌中制霉菌素聚酮合酶进行操作，获得了两种在C31和C33位带有羟基的制霉菌素类似物。通过核磁共振（NMR）确定了类似物的结构，发现它们的溶解度比制霉菌素高2000倍以上。然而，两种类似物均显示失去了抗真菌活性，这意味着制霉菌素分子疏水多烯区域的完整性对于杀菌作用至关重要。对新类似物进行的NMR数据和计算机建模表明存在构象变化以及结构无序性显著增加，这可能解释了溶解度增加和活性丧失的原因。
