Abstract
Fission yeast contains three essential β(1,3)-D-glucan synthases (GSs), Bgs1, Bgs3, and Bgs4, with non-overlapping roles in cell integrity and morphogenesis. Only the bgs4+ mutants pbr1-8 and pbr1-6 exhibit resistance to GS inhibitors, even in the presence of the wild-type (WT) sequences of bgs1+ and bgs3+. Thus, Bgs1 and Bgs3 functions seem to be unaffected by those GS inhibitors. To learn more about echinocandins’ mechanism of action and resistance, cytokinesis progression and cell death were examined by time-lapse fluorescence microscopy in WT and pbr1-8 cells at the start of treatment with sublethal and lethal concentrations of anidulafungin, caspofungin, and micafungin. In WT, sublethal concentrations of the three drugs caused abundant cell death that was either suppressed (anidulafungin and micafungin) or greatly reduced (caspofungin) in pbr1-8 cells. Interestingly, the lethal concentrations induced differential phenotypes depending on the echinocandin used. Anidulafungin and caspofungin were mostly fungistatic, heavily impairing cytokinesis progression in both WT and pbr1-8. As with sublethal concentrations, lethal concentrations of micafungin were primarily fungicidal in WT cells, causing cell lysis without impairing cytokinesis. The lytic phenotype was suppressed again in pbr1-8 cells. Our results suggest that micafungin always exerts its fungicidal effect by solely inhibiting Bgs4. In contrast, lethal concentrations of anidulafungin and caspofungin cause an early cytokinesis arrest, probably by the combined inhibition of several GSs.
Highlights
Owing to the increasing population of immunocompromised patients, life-threatening systemic fungal infections have become a major risk for public health
Because the imaging and preparation of yeast cells for time-lapse fluorescence microscopy requires cultures containing a higher density of cells than cultures used for visualizing the presence or absence of growth in susceptibility assays, we compared the susceptibilities to echinocandins of the WT and pbr1-8 strains in cultures inoculated either with a typical lower cell density (5 × 105 cells/mL) or with a higher cell density
Our results indicate that all three echinocandins appear to act via Bgs4
Summary
Owing to the increasing population of immunocompromised patients, life-threatening systemic fungal infections have become a major risk for public health. A weakened immune system because of illnesses, such as cancer, diabetes, or HIV/AIDS syndrome, together with the practice of treatments or medicines, such as chemotherapy, organ transplantation, or corticoids, might predispose the afflicted to secondary fungal infections [1,2,3]. It has been estimated that over 1.6 million people die each year because of severe fungal infections [1,4]. Four classes of antifungal drugs (echinocandins, polyenes, pyrimidine analogues, and triazoles) are used for treating systemic fungal infections [5,6,7]. The problem of systemic fungal infections is worsened by the emergence of fungi resistant to one or several classes of the available antifungals [8,9].
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