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Metabolic Mediation of Antifungal Toxicity
Author(s) -
Cabral Damien,
Belenky Peter
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.928.2
Subject(s) - nad+ kinase , toxicity , amphotericin b , sirtuin , biology , dna damage , candida albicans , pharmacology , biochemistry , microbiology and biotechnology , chemistry , dna , enzyme , antifungal , organic chemistry
Therapy with the potent antifungal amphotericin B is significantly impacted by dose limiting toxicity to host cells. Thus, to improve the efficacy of this antifungal, we must understand the molecular toxicology for both the target fungi and the mammalian host. Previous work has shown that fungicidal drugs, such as amphotericin B, induce DNA damage in fungal and mammalian cells, leading to considerable cytotoxic effects. Therefore, modulating the susceptibility of cells to DNA damage may provide a mechanism of fine‐tuning antifungal efficacy and reducing side effects. In both fungal and mammalian cells, NAD‐dependent histone deacetylases, or “sirtuins”, play a central role in the induction of apoptosis in response to genotoxic agents. Inducing sirtuin activity by elevating cellular NAD levels leads to reduced cellular death and improved protection from various forms of stress in fungi and mammals. We found that treatment of human embryonic kidney cells, a primary target of amphotericin B toxicity, with NAD precursors provides protection against amphotericin B toxicity. However, treatment of C. albicans with the same precursors did not alter toxicity, suggesting that modulating NAD levels may have a differential impact between fungi and mammals. Furthermore, decreasing intracellular NAD levels using FK866 increases amphotericin B toxicity in HEK293 cells, further suggesting a link between NAD metabolism and susceptibility to antifungals in mammals. Therefore, it is possible that we can identify novel therapeutic methodologies that improve antifungal efficacy while reducing toxic side effects by exploiting the innate differences in fungal and mammalian NAD metabolism. Support or Funding Information Research reported in this abstract was supported in full by an Institutional Development Award (IDeA) Network for Biomedical Research Excellence from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103430