Structure-Antifungal Activity Relationships of Polyene Antibiotics of the Amphotericin B Group

Abstract

A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10. Antibiotics with OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH 3 or COOH group in the position C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis sepsis in leukopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (compound 3n) and, especially, L-glutamate of 2-(N,N-dimethylamino)ethyl amide of S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties.

A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage

“…The samples were treated according to our previous report 33 In order to quickly establish mouse model of disseminated candidiasis, all mice used in this study were received CY at 100 mg/kg body weight administered intraperitoneally 3 days before and 1 day after infection 38 . Fungal suspension (C. albicans: 2 × 10 5 CFU/mouse in volume of 0.1 mL) was inoculated into the lateral tail vein of mice, 3 days (72 h) after the intraperitoneal injection of CY.…”

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

“…Burke and coworkers have developed a scalable chemical method for converting amphotericin B to valuable derivatives in which substituted ureas replace the free carboxyl group at C-16 (Davis et al, 2015). Chemical and biological methods can complement one another (Tevyashova et al, 2013). Murata and co-workers have made two new amphotericins by reducing the 7-keto group in biosynthetically engineered 7-oxoamphotericin B, and separating the two stereoisomers of 7-hydroxy-amphotericin B (Yamamoto et al, 2015).…”

Structural modifications and yield improvements of polyene macrolide antibiotics

“…例如, 化学衍生获得的7-酮基-7-去羟 基两性霉素B(20)在溶血毒性大幅下降的同时, 其抗 真菌活性同样较两性霉素B下降了约8倍(表1) [29] . 综 合七烯抗生素的多元醇区域结构改造数据可以发现, 当衍生物C8及C9位或C7及C10位为羟基时, 衍生物 抗真菌活性相对较高; 当衍生物C7及C9位为羟基时, 衍生物抗真菌活性则相对较低 [29,40] .…”