Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

作者：Shrestha Sanjib K; Foss Marina Y; Green Keith D; Garneau Tsodikova Sylvie

来源：Antimicrobial Agents and Chemotherapy, 2015, 59(8): 4861-4869.

DOI：10.1128/AAC.00229-15

In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6 ''-position in a thioether linkage exhibited chain length-dependent antiftingal activities. Analogues with C-12 and C-14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C-4, C-6, and C-8, TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC(50)s) for the most potent TOB analogues (C-12 and C-14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C-12 and C-14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs.

• 出版日期2015-8