Synthesis and Bioactivities of Kanamycin B-Derived Cationic Amphiphiles.
Synthesis and Bioactivities of Kanamycin B-Derived Cationic Amphiphiles.
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卡纳米霉素B衍生的阳离子两亲物的合成和生物活性。
DOI：
10.1021/acs.jmedchem.5b01375
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发表时间：
2015-12-10
影响因子：
7.3
通讯作者：
Gameau-Tsodikova, Sylvie
中科院分区：
文献类型：
--
作者：
Fosso, Marina Y.;Shrestha, Sanjib K.;Green, Keith D.;Gameau-Tsodikova, Sylvie
衍生自氨基糖苷类（AG）的阳离子两亲物已显示出增强的抗微生物活性。通过在AG主链上连接诸如线性烷基链的疏水残基，已经开发出具有新颖作用机制的有趣的抗细菌和抗真菌剂。本文报道了七个卡那霉素B（KAN B）衍生物的设计与合成。还研究了它们的抗菌和抗真菌活性，沿着抗性/酶促、溶血和细胞毒性测定。其中两个化合物的C12和C14脂肪链通过硫醚键连接在KANB的6″-位上，具有良好的抗菌和抗真菌活性，对于几种AG修饰酶来说，它们是比KANB差的底物，并且可以延迟细菌和真菌的耐药性的发展。而且，它们的溶血性都比已知的膜靶向抗生素短杆菌肽和已知的抗真菌剂阿替霉素B相对更低，并且在它们的抗真菌MIC值下没有毒性。它们氧化成砜也被证明对其活性没有影响。此外，它们都与泊沙康唑（一种目前用于治疗人类真菌感染的唑类药物）协同作用。
Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein, we report the design and synthesis of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal activities, along with resistance/enzymatic, hemolytic, and cytotoxicity assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position of KANB through a thioether linkage, exhibited good antibacterial and antifungal activity, were poorer substrates than KANB for several AG-modifying enzymes, and could delay the development of resistance in bacteria and fungi. Also, they were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections.
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影响因子：
7.3
作者：
Hanessian, Stephen;Szychowski, Janek;Westhof, Eric
通讯作者：
Westhof, Eric
影响因子：
7.3
作者：
Bera, Smritilekha;Zhanel, George G.;Schweizer, Frank
通讯作者：
Schweizer, Frank
影响因子：
3.3
作者：
Chang, Cheng-Wei T.;Fosso, Marina;Takemoto, Jon Y.
通讯作者：
Takemoto, Jon Y.
影响因子：
3.2
作者：
Houghton, Jacob L.;Biswas, Tapan;Garneau-Tsodikova, Sylvie
通讯作者：
Garneau-Tsodikova, Sylvie
影响因子：
2.9
作者：
Chen W;Green KD;Tsodikov OV;Garneau-Tsodikova S
通讯作者：
Garneau-Tsodikova S