Repurposing the FDA‐approved anticancer agent ponatinib as a fluconazole potentiator by suppression of multidrug efflux and Pma1 expression in a broad spectrum of yeast species. Issue 2 (6th May 2021)

• Record Type: Journal Article
• Authors: Liu, Lin; Jiang, Tong; Zhou, Jia; Mei, Yikun; Li, Jinyang; Tan, Jingcong; Wei, Luqi; Li, Jingquan; Peng, Yibing; Chen, Changbin; Liu, Ning‐Ning; Wang, Hui
• Other Names: Guo Jinshan guestEditor.
• Is Part Of: Microbial biotechnology. Volume 15:Issue 2(2022)
• Page Start: 482
• Page End: 498
• Publication Date: 2021-05-06
• Subjects: Microbial biotechnology -- Periodicals; Biotechnology; Microbiology; 660.62
• DOI: 10.1111/1751-7915.13814
• Languages: English
• ISSNs: 1751-7915

Abstract

Summary: Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further aggravates the current situation resulting in a growing challenge in medical mycology. Here, we identified that ponatinib, an FDA‐approved antitumour drug, significantly enhanced the activity of the azole fluconazole, the most widely used antifungal drug. Further detailed investigation of ponatinib revealed that its combination with fluconazole displayed broad‐spectrum synergistic interactions against a variety of human fungal pathogens such as Candida albicans, Saccharomyces cerevisiae and Cryptococcus neoformans . Mechanistic insights into the mode of action unravelled that ponatinib reduced the efflux of fluconazole via Pdr5 and suppressed the expression of the proton pump, Pma1. Taken together, our study identifies ponatinib as a novel antifungal that enhances drug activity of fluconazole against diverse fungal pathogens. Abstract : Model depiction of the role of ponatinib in potentiation of the antifungal efficacy of fluconazole by inhibition of fluconazole efflux via Pdr5 and suppression of Pma1 expression. Ponatinib (PubChem CID: 24826799) promotes intracellular fluconazole (PubChem CID:3365) accumulation by binding to Pdr5. On the other hand, ponatinib perturbs the cytosolic pH homeostasis by inhibiting the proton pump Pma1 located at the plasma membrane. Eventually, the dual action of ponatinib through these two pathways leads to cell death.