Department of Chemistry, University of California, San Diego, 9500 Gilman Drive MC0358, La Jolla, CA 92093, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive MC0358, La Jolla, CA 92093, USA.
Mar Drugs. 2019 Feb 7;17(2):102. doi: 10.3390/md17020102.
Bengazoles A⁻G from the marine sponge sp. exhibit potent in vitro antifungal activity against spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from sp. The MOA of bengazole A was further explored by monitoring the sterol composition of in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of in the presence of clotrimazole-a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase-showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative.
来自海洋海绵 sp.的苯并唑 A-G 表现出对 spp. 和其他致病真菌的强大体外抗真菌活性。在液体培养和 Mueller-Hinton 琼脂表面培养下，研究了苯并唑 A 在 下的作用机制 (MOA)。在苯并酰胺 A 的存在下，观察到苯并唑 A 具有明显的剂量依赖性协同抗真菌活性，苯并酰胺 A 也是来自 sp. 的天然产物。通过监测亚致死浓度下苯并唑 A 存在时 的甾醇组成，进一步探索了苯并唑 A 的 MOA。在存在氯康唑的情况下从液体培养物中制备的溶剂提取物的 GCMS-一种临床上批准的唑类抗真菌药物，通过抑制 14α-脱甲基酶抑制麦角固醇生物合成-显示出降低的细胞麦角固醇含量和增加的羊毛甾醇和 24-亚甲基二氢羊毛甾醇（麦角固醇生物合成的分流代谢物）浓度。当用苯并唑 A 培养 时，观察到相对甾醇组成没有变化。这些结果排除了苯并唑类的唑类 MOA，表明存在另一种尚未确定的作用机制。
