Steinbuch Kfir B, Benhamou Raphael I, Levin Lotan, Stein Reuven, Fridman Micha
School of Chemistry, Raymond and Beverley Sackler Faculty of Exact Sciences , Tel Aviv University , Tel Aviv , Israel 6997801.
Department of Neurobiology, George S. Wise Faculty of Life Sciences , Tel Aviv University , Ramat Aviv , Tel Aviv , Israel 6997801.
ACS Infect Dis. 2018 May 11;4(5):825-836. doi: 10.1021/acsinfecdis.7b00272. Epub 2018 Feb 15.
Antimicrobial cationic amphiphiles derived from aminoglycosides act through cell membrane permeabilization but have limited selectivity for microbial cell membranes. Herein, we report that an increased degree of unsaturation in the fatty acid segment of antifungal cationic amphiphiles derived from the aminoglycoside tobramycin significantly reduced toxicity to mammalian cells. A collection of tobramycin-derived cationic amphiphiles substituted with C lipid chains varying in degree of unsaturation and double bond configuration were synthesized. All had potent activity against a panel of important fungal pathogens including strains with resistance to a variety of antifungal drugs. The tobramycin-derived cationic amphiphile substituted with linolenic acid with three cis double bonds (compound 6) was up to an order of magnitude less toxic to mammalian cells than cationic amphiphiles composed of lipids with a lower degree of unsaturation and than the fungal membrane disrupting drug amphotericin B. Compound 6 was 12-fold more selective (red blood cell hemolysis relative to antifungal activity) than compound 1, the derivative with a fully saturated lipid chain. Notably, compound 6 disrupted the membranes of fungal cells without affecting the viability of cocultured mammalian cells. This study demonstrates that the degree of unsaturation and the configuration of the double bond in lipids of cationic amphiphiles are important parameters that, if optimized, result in compounds with broad spectrum and potent antifungal activity as well as reduced toxicity toward mammalian cells.
源自氨基糖苷类的抗菌阳离子两亲物通过细胞膜通透作用发挥作用，但对微生物细胞膜的选择性有限。在此，我们报告称，源自氨基糖苷类妥布霉素的抗真菌阳离子两亲物脂肪酸链段不饱和度的增加显著降低了对哺乳动物细胞的毒性。合成了一系列用不饱和度和双键构型不同的C脂质链取代的妥布霉素衍生阳离子两亲物。它们对一组重要的真菌病原体均具有强效活性，包括对多种抗真菌药物耐药的菌株。用含有三个顺式双键的亚麻酸取代的妥布霉素衍生阳离子两亲物（化合物6）对哺乳动物细胞的毒性比由不饱和度较低的脂质组成的阳离子两亲物以及真菌膜破坏药物两性霉素B低一个数量级。化合物6的选择性（相对于抗真菌活性的红细胞溶血）是化合物1（具有完全饱和脂质链的衍生物）的12倍。值得注意的是，化合物6破坏真菌细胞膜而不影响共培养的哺乳动物细胞的活力。这项研究表明，阳离子两亲物脂质中双键的不饱和度和构型是重要参数，如果进行优化，可得到具有广谱强效抗真菌活性且对哺乳动物细胞毒性降低的化合物。
