Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

Authors

Sanjib K. Shrestha, University of KentuckyFollow
Marina Y. Fosso, University of KentuckyFollow
Keith D. Green, University of KentuckyFollow
Sylvie Garneau-Tsodikova, University of KentuckyFollow

Abstract

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 antifungal activities. Analogues with C₁₂ and C₁₄ 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, C₄, C₆, and C₈ TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC₅₀s) for the most potent TOB analogues (C₁₂ and C₁₄) 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 C₁₂ and C₁₄ 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.

Document Type

Article

Publication Date

8-2015

Notes/Citation Information

Published in Antimicrobial Agents and Chemotherapy, v. 59, no. 8, p. 4861-4869.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The copyright holders have granted the permission for posting the article here.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1128/AAC.00229-15

Funding Information

This work was supported by National Institutes of Health (NIH) grant AI090048 (S.G.-T.) and by startup funds from the College of Pharmacy at the University of Kentucky (S.G.-T.).

Repository Citation

Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.; and Garneau-Tsodikova, Sylvie, "Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents" (2015). Pharmaceutical Sciences Faculty Publications. 64.
https://uknowledge.uky.edu/ps_facpub/64