美国伊利诺伊大学Martin D. Burke和威斯康星大学麦迪逊分校Chad M. Rienstra研究组合作表明，调整甾醇提取动力学可生成一种保护肾脏的多烯类抗真菌药物。2023年11月8日出版的《自然》发表了这项成果。

研究人员展示了快速、有选择性地提取真菌麦角甾醇可以产生强效、保护肾脏的多烯类抗真菌药物。研究发现，胆固醇提取可降低两性霉素B对人类肾脏细胞的毒性。研究人员对无固醇和固醇结合状态下两性霉素B海绵状聚集体的高分辨率结构进行了研究，发现了一种很有前景的结构衍生物，它不与胆固醇结合，因此对肾脏没有影响。这种衍生物提取麦角甾醇的速度较慢，因此药效也较弱。

通过第二次结构改造选择性地加速麦角甾醇的提取，研究人员得到了一种新的多烯烃：AM-2-19，它对小鼠和原代人类肾细胞无肾脏损害，对数百种致病真菌菌株有特效，在体外可抵抗真菌入侵，在侵袭性真菌感染动物模型中具有很好的疗效。因此，合理调整小分子之间相互作用的动力学可能会带来更好的治疗方法，用于治疗导致数百万人死亡的真菌感染以及研发其他潜在的抗药性侵袭性抗菌药物，包括最近证明可通过靶向特定脂质超分子结构发挥作用的抗菌药物。

据介绍，几十年来，人们一直在努力研发可保护肾脏的多烯类抗真菌药物，但却为经典的膜渗透模型所误导。最近，人们发现在临床上发挥重要作用但同时也具有高肾毒性的小分子，天然产物两性霉素B主要通过形成膜外海绵状聚集体的形式从脂质双分子层中提取麦角固醇，从而杀死真菌。

附：英文原文

Title: Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal

Author: Maji, Arun, Soutar, Corinne P., Zhang, Jiabao, Lewandowska, Agnieszka, Uno, Brice E., Yan, Su, Shelke, Yogesh, Murhade, Ganesh, Nimerovsky, Evgeny, Borcik, Collin G., Arango, Andres S., Lange, Justin D., Marin-Toledo, Jonnathan P., Lyu, Yinghuan, Bailey, Keith L., Roady, Patrick J., Holler, Jordan T., Khandelwal, Anuj, SantaMaria, Anna M., Sanchez, Hiram, Juvvadi, Praveen R., Johns, Gina, Hageman, Michael J., Krise, Joanna, Gebremariam, Teclegiorgis, Youssef, Eman G., Bartizal, Ken, Marr, Kieren A., Steinbach, William J., Ibrahim, Ashraf S., Patterson, Thomas F., Wiederhold, Nathan P., Andes, David R., Pogorelov, Taras V., Schwieters, Charles D., Fan, Timothy M., Rienstra, Chad M., Burke, Martin D.

Issue&Volume: 2023-11-08

Abstract: Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2–6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9. A study reports the development of a structural derivative of amphotericin B with broad antifungal activity in mice but without the renal toxicity associated with amphotericin B.

DOI: 10.1038/s41586-023-06710-4

Source: https://www.nature.com/articles/s41586-023-06710-4