Antifungal Activities and Mode of Action of Amphiphilic Tobramycin Analogues and Their Synergistic Interactions with Azoles Against Candida albicans

S. Shrestha

Author address: 

Univ. of Kentucky, Lexington, KY

Abstract: 

Background: Invasive fungal infections, such as candidiasis, have become a major cause of morbidity and mortality, especially among immunocompromised patients worldwide. Azoles are widely used antifungals to treat these infections in humans. But the increasing frequency of cross-resistance against azoles requires improved therapeutic strategies. Previously, it was shown that amphiphilic tobramycin analogues with the linear alkyl chain of C4-C14 exhibited chainlength dependent antibacterial activities but their antifungal profile is unexplored. Besides, combination therapy has become popular in clinical practice as a potential strategy to fight resistant fungal isolates. The aim of this study was to investigate the antifungal properties and mechanism of action of novel amphiphilic tobramycin analogues and their synergistic interactions with four azoles against C. albicans. Methods: The MICs of TOB analogues against yeast cells were determined as described in CLSI document M27-A3. The fungal membranedisruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. Checkerboard assays were used to assess synergistic, indifferent and antagonistic effects, with C12 and C14 used in combination with four azoles by calculating fractional inhibitory concentration indices. Time kill curve assays were performed by colony counting at different time points.Results: C12 and C14 showed broad-spectrum antifungal activities against yeast and filamentous fungi. with the MIC values ranged from 1.95 to 31.2 μg/mL and 1.95 to 7.8 μg/mL, respectively. Our data suggests that the fungicidal mechanism of action of C12 and C14 appears to involve the perturbation of fungal membranes. Strikingly, majority of C. albicans strains were synergistically inhibited by C12 and C14 when combined with all four azoles (FLC, ITC, POS and VOR) except in few cases. Finally, synergism between C12 / C14 and POS were confirmed by time-kill assay.Conclusions: In conclusion, C12 and C14 showed broad-spectrum antifungal activities against yeasts and filamentous fungi that appear to target fungal plasma membrane. They also showed potent antifungal synergism with azoles which suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency.
2016

abstract No: 

SUNDAY-427

Full conference title: 

ASM Microbe 2016
    • ASM microbe 1st (2016)