Amphotericin B has been the gold standard for the treatment of invasive mycosis for many years. Its resistance mechanisms are reported to be mainly related to the decrease of ergosterol content or the changes of cell wall. Previous study has shown that Saccharomyces cerevisiae strain lack of BSC2 was sensitive significantly to Amphotericin B. In the present study, the role of BSC2 on Amphotericin B resistance were investigated. We found that BSC2 enhanced the resistance of yeast cells to Amphotericin B, which was not related to cellular ergosterol content. BSC2 can maintain the permeability of mitochondrial membrane and cell membrane integrity by inhibiting the accumulation of intercellular reactive oxygen species and alleviating the production of lipid peroxidation and superoxide radical. These alterations were attributed to the enhancement of the activities of superoxide dismutase, catalase and glutathione peroxidase, and the increased glutathione content. Taken together, BSC2 inhibits oxidative damage induced by Amphotericin B through increasing activities of antioxidant enzymes and levels of GSH to alleviate the accumulation of reactive oxygen species, lipid peroxidation and superoxide radical, resulting in the maintenance of mitochondrial membrane potential and cell membrane integrity. However, Amphotericin B resistance mediated by BSC2 is independent of Yap1p, GSH1 and Hog1p. The results demonstrate for the first time that BSC2 enhances cell resistance to Amphotericin B by inhibiting oxidative damage in yeast. Our findings improve current understanding of the mechanism of Amphotericin B resistance and provide potential strategy for reducing Amphotericin B resistance.
Zhiwei Huang,Hongsheng Dai,Xiaoyu Zhang,Qiao Wang,Jing Sun,Yunxia Deng,Ping Shi
Biofilm plays an important role in fungal multidrug resistance (MDR). Our previous studies showed that BSC2 is involved in resistance to amphotericin B (AMB) through antioxidation in Saccharomyces cerevisiae . In this study, the overexpression of BSC2 and IRC23 induced strong MDR in S. cerevisiae . BSC2 -overexpression affected cellular flocculation, cell surface hydrophobicity, biofilm formation and invasive growth. However, it failed to induce caspofungin (CAS) resistance and affect the invasive growth in FLO mutant strains ( FLO11 Δ, FLO1 Δ, FLO8 Δ and TUP1 Δ). Furthermore, the overexpression of BSC2 compensated for chitin synthesis defects to maintain the cell wall integrity and significantly reduced the cell morphology abnormality induced by CAS. However, it could not repair the cell wall damage caused by CAS in the FLO mutant strains. Although BSC2 overexpression increased the level of mannose in the cell wall, DPM1 overexpression in both BY4741 and bsc2 ∆ could confer resistance to CAS and AMB. In addition, BSC2 overexpression significantly increased the mRNA expression of FLO11 , FLO1 , FLO8 and TUP1 . BSC2 may function as a regulator of FLO genes and be involved in cell wall integrity in yeast. Taken together, our data demonstrate that BSC2 induces MDR in a FLO pathway-dependent manner via contributing to the formation of biofilms in S. cerevisiae . Take Aways Overexpression of BSC2 induced strong MDR in S. cerevisiae . BSC2 affected cellular flocculation, CSH, biofilm formation and invasive growth. BSC2 could not repair the cell wall damage caused by CAS in the FLO mutants. BSC2 may function as a regulator of FLO genes to maintain cell wall integrity. BSC2 promotes biofilm formation in a FLO pathway-dependent manner to induce MDR.
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