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New Application of Neomycin B–Bisbenzimidazole Hybrids as Antifungal Agents
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-12-11 00:00:00 , DOI: 10.1021/acsinfecdis.7b00254 Nishad Thamban Chandrika 1 , Sanjib K Shrestha 1 , Nihar Ranjan 2 , Anindra Sharma 2 , Dev P Arya 2 , Sylvie Garneau-Tsodikova 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2017-12-11 00:00:00 , DOI: 10.1021/acsinfecdis.7b00254 Nishad Thamban Chandrika 1 , Sanjib K Shrestha 1 , Nihar Ranjan 2 , Anindra Sharma 2 , Dev P Arya 2 , Sylvie Garneau-Tsodikova 1
Affiliation
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Alkylated aminoglycosides and bisbenzimidazoles have previously been shown to individually display antifungal activity. Herein, we explore for the first time the antifungal activity (in liquid cultures and in biofilms) of ten alkylated aminoglycosides covalently linked to either mono- or bisbenzimidazoles. We also investigate their toxicity against mammalian cells, their hemolytic activity, and their potential mechanism(s) of action (inhibition of fungal ergosterol biosynthetic pathway and/or reactive oxygen species (ROS) production). Overall, many of our hybrids exhibited broad-spectrum antifungal activity. We also found them to be less cytotoxic to mammalian cells and less hemolytic than the FDA-approved antifungal agents amphotericin B and voriconazole, respectively. Finally, we show with our best derivative (8) that the mechanism of action of our compounds is not the inhibition of ergosterol biosynthesis, but that it involves ROS production in yeast cells.
中文翻译：
新霉素B-双苯并咪唑杂化物作为抗真菌药物的新应用
烷基化氨基糖苷类和双苯并咪唑类药物此前已被证明具有各自的抗真菌活性。在此，我们首次探索了与单苯并咪唑或双苯并咪唑共价连接的十种烷基化氨基糖苷的抗真菌活性（在液体培养物和生物膜中）。我们还研究了它们对哺乳动物细胞的毒性、溶血活性及其潜在的作用机制（抑制真菌麦角甾醇生物合成途径和/或活性氧（ROS）产生）。总体而言，我们的许多杂交品种表现出广谱抗真菌活性。我们还发现它们对哺乳动物细胞的细胞毒性和溶血性分别低于 FDA 批准的抗真菌药物两性霉素 B 和伏立康唑。最后，我们用我们最好的衍生物（ 8 ）证明我们的化合物的作用机制不是抑制麦角甾醇生物合成，而是涉及酵母细胞中ROS的产生。
更新日期：2017-12-11
中文翻译：
新霉素B-双苯并咪唑杂化物作为抗真菌药物的新应用
烷基化氨基糖苷类和双苯并咪唑类药物此前已被证明具有各自的抗真菌活性。在此，我们首次探索了与单苯并咪唑或双苯并咪唑共价连接的十种烷基化氨基糖苷的抗真菌活性（在液体培养物和生物膜中）。我们还研究了它们对哺乳动物细胞的毒性、溶血活性及其潜在的作用机制（抑制真菌麦角甾醇生物合成途径和/或活性氧（ROS）产生）。总体而言，我们的许多杂交品种表现出广谱抗真菌活性。我们还发现它们对哺乳动物细胞的细胞毒性和溶血性分别低于 FDA 批准的抗真菌药物两性霉素 B 和伏立康唑。最后，我们用我们最好的衍生物（ 8 ）证明我们的化合物的作用机制不是抑制麦角甾醇生物合成，而是涉及酵母细胞中ROS的产生。
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