Treshchalin I D, Sletta H, Borgos S E, Pereverzeva E P, Voeĭkova T A, Ellingsen T E, Zotchev S B
Antibiot Khimioter. 2005;50(7):18-22.
New polyene macrolide S44HP was purified from the culture of recombinant Streptomyces noursei strain with engineered nystatin polyketide synthase. S44HP, nystatin (NYS), and amphotericin B (Amph-B) were tested against 19 clinical fungal isolates in agar diffusion assay, which demonstrated clear differences in antifungal activities of these antibiotics. Sodium deoxycholate suspensions of all three antibiotics were subjected to acute toxicity studies in vivo upon intravenous administration in mice. NYS exhibited the lowest acute toxicity in mice in these experiments, while both Amph-B and S44HP were shown to be 4 times more toxic as judged from the LD50 values. While the acute toxicity of S44HP was higher than that of Amph-B, the data analysis revealed a significantly increased LD10 to LD50 dose interval for S44HP compared to Amph-B. The data revealed structural features of polyene macrolides, which might have an impact on both the activity and toxicity profiles of these antibiotics. These results represent the first example of preclinical evaluation of an "engineered" polyene macrolide, and can be valuable for rational design of novel antifungal drugs with improved pharmacological properties.
新型多烯大环内酯类抗生素S44HP是从经工程改造的制霉菌素聚酮合酶的重组诺尔斯链霉菌菌株培养物中纯化得到的。在琼脂扩散试验中，对S44HP、制霉菌素（NYS）和两性霉素B（Amph-B）针对19株临床真菌分离株进行了测试，结果表明这些抗生素的抗真菌活性存在明显差异。对这三种抗生素的脱氧胆酸钠悬浮液进行了小鼠静脉注射的体内急性毒性研究。在这些实验中，NYS在小鼠中表现出最低的急性毒性，而根据半数致死量（LD50）值判断，Amph-B和S44HP的毒性均高出4倍。虽然S44HP的急性毒性高于Amph-B，但数据分析显示，与Amph-B相比，S44HP的最小致死量（LD10）至半数致死量（LD50）的剂量间隔显著增加。数据揭示了多烯大环内酯类抗生素的结构特征，这可能对这些抗生素的活性和毒性特征均有影响。这些结果代表了对“工程化”多烯大环内酯类抗生素进行临床前评估的首个实例，对于合理设计具有改善药理特性的新型抗真菌药物具有重要价值。
