Abstract
Amphiphilic kanamycins derived from the classic antibiotic kanamycin have attracted interest due to their novel bioactivities beyond inhibition of bacteria. In this study, the recently described 4″,6″-diaryl amphiphilic kanamycins reported as inhibitors of connexin were examined for their antifungal activities. Nearly all 4″,6″-diaryl amphiphilic kanamycins tested had antifungal activities comparable to those of 4″,6″-dialkyl amphiphilic kanamycins, reported previously against several fungal strains. The minimal growth inhibitory concentrations (MICs) correlated with the degree of amphiphilicity (cLogD) of the di-substituted amphiphilic kanamycins. Using the fluorogenic dyes, SYTOXTM Green and propidium iodide, the most active compounds at the corresponding MICs or at 2×MICs caused biphasic dye fluorescence increases over time with intact cells. Further lowering the concentrations to half MICs caused first-order dye fluorescence increases. Interestingly, 4×MIC or 8×MIC levels resulted in fluorescence suppression that did not correlate with the MIC and plasma membrane permeabilization. The results show that 4″,6″-diaryl amphiphilic kanamycins are antifungal and that amphiphilicity parameter cLogD is useful for the design of the most membrane-active versions. A cautionary limitation of fluorescence suppression was revealed when using fluorogenic dyes to measure cell-permeation mechanisms with these antifungals at high concentrations. Finally, 4″,6″-diaryl amphiphilic kanamycins elevate the production of cellular reactive oxygen species as other reported amphiphilic kanamycins.
Highlights
IntroductionFungal diseases cause tremendous economic loss and health impacts globally
Commonly unappreciated, fungal diseases cause tremendous economic loss and health impacts globally
We have examined the antifungal activities of 4”,6”-diaryl kanamycins, as well as the previously described 4”,6”-dialkyl kanamycins
Summary
Fungal diseases cause tremendous economic loss and health impacts globally. The death rate from fungal diseases is equal to that of tuberculosis and malaria combined, with approximately 10% of those deaths due to cryptococcal meningitis [1,2]. Immunosuppressed individuals, such as those infected with HIV or undergoing treatment for cancer or organ transplants, are especially susceptible to invasive fungal infections. Current treatment options for fungal infections include polyene-based compounds (e.g., amphotericin B) [3,4,5], cytosine-based compounds (e.g., flucytosine) [5,6], and azole-based compounds (e.g., itraconazole and fluconazole) [5,7,8]. Further research to develop new and effective treatments for fungal diseases is urgent
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