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.
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.
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通过抑制多种酵母物种中的多药外排和 Pma1 表达，将 FDA 批准的抗癌药物 ponatinib 重新用作氟康唑增效剂。
DOI：
10.1111/1751-7915.13814
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发表时间：
2022-03
影响因子：
5.7
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Liu L;Jiang T;Zhou J;Mei Y;Li J;Tan J;Wei L;Li J;Peng Y;Chen C;Liu NN;Wang H
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. 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.
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影响因子：
30.3
作者：
Chen C;Pande K;French SD;Tuch BB;Noble SM
通讯作者：
Noble SM
影响因子：
14.8
作者：
Anderson TM;Clay MC;Cioffi AG;Diaz KA;Hisao GS;Tuttle MD;Nieuwkoop AJ;Comellas G;Maryum N;Wang S;Uno BE;Wildeman EL;Gonen T;Rienstra CM;Burke MD
通讯作者：
Burke MD
影响因子：
64.5
作者：
Brown JCS;Nelson J;VanderSluis B;Deshpande R;Butts A;Kagan S;Polacheck I;Krysan DJ;Myers CL;Madhani HD
通讯作者：
Madhani HD
DOI：
10.1073/pnas.78.4.2125
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
GILLIES, RJ;UGURBIL, K;SHULMAN, RG
通讯作者：
SHULMAN, RG
影响因子：
4.8
作者：
Flanagan PR;Liu NN;Fitzpatrick DJ;Hokamp K;Köhler JR;Moran GP
通讯作者：
Moran GP