Molecular mechanism of fluconazole resistance and pathogenicity attributes of Lebanese Candida albicans hospital isolates
2021
Fattouh, Nour | Hdayed, Dana | Geukgeuzian, Geovanni | Tokajian, Sima | Khalaf, Roy A.
Hospital infections caused by the opportunistic fungus Candida albicans are increasingly common and life threatening. The first line of defense consists of administering antifungal drugs such as azoles including fluconazole that prevent ergosterol biosynthesis. C. albicans is rapidly developing resistance towards antifungal drugs through various mechanisms including mutations in ERG11 which is a gene involved in the ergosterol biosynthesis pathway. These mutations prevent the binding of the drug and inactivate ergosterol synthesis. Alternatively, upregulation of cell membrane ergosterol content generates resistance by countering the effect of the drug. In this study we sequenced the ERG11 gene in 6 fluconazole sensitive and 8 fluconazole resistant C. albicans isolates recovered from clinical settings in Lebanon and quantified the ergosterol content of their plasma membranes to identify mechanisms linked to fluconazole resistance. A number of pathogenicity attributes were also analyzed to determine any correlation with fluconazole resistance. Our results revealed an increase in ergosterol content in the fluconazole resistant isolates. In addition, we identified both novel and previously reported amino acid substitutions in ERG11 as well as frameshift mutations that might contribute to resistance. The fluconazole resistant isolates did not exhibit an increased virulence potential in a mouse model of systemic infection and showed decreased in vitro potential to form biofilms. No discrepancy between drug resistant and sensitive isolates to cell surface disrupting agents was observed. This approach is the first of its kind to be carried out in Lebanon to identify possible mechanisms and phenotypes of drug resistant C. albicans isolates.
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