A dual action small molecule enhances azoles and overcomes resistance through co-targeting Pdr5 and Vma1
A dual action small molecule enhances azoles and overcomes resistance through co-targeting Pdr5 and Vma1
复制标题
双重作用小分子通过共同靶向 Pdr5 和 Vma1 增强唑类药物并克服耐药性
DOI：
10.1016/j.trsl.2022.04.002
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发表时间：
2022
影响因子：
7.8
通讯作者：
Hu
中科院分区：
文献类型：
--
作者：
Ning-Ning Liu;Jia Zhou;Tong Jiang;Maureen Tarsio;Feifei Yu;Xuehan Zheng;Wanjun Qi;Lin Liu;Jing-Cong Tan;Luqi Wei;Jun Ding;Jingquan Li;Lingbing Zeng;Biao Ren;Xiaotian Huang;Yibing Peng;Yong-Bing Cao;Yanbin Zhao;Xin-Yu Zhang;Patricia M Kane;Changbin Chen;Hu
由于抗真菌药物有限和耐药性的迅速出现，真菌感染威胁着全世界的人类健康。表皮生长因子受体（EGFR）被证明介导上皮细胞内吞的主要人类真菌病原体，白色念珠菌。然而，EGFR抑制剂是否对真菌细胞起作用仍然未知。在这里，我们发现特异性EGFR抑制剂甲磺酸奥希替尼（OSI）增强了唑类药物对多种真菌病原体的疗效，并克服了唑类药物耐药性。机制研究揭示了OSI的保守活性，通过抑制Pdr 5促进细胞内氟康唑积累，并通过靶向丝氨酸274处的Vma 1破坏V-ATP酶功能，最终导致全局调节因子TOR失活。体内药效和毒性评价表明，OSI在抑制氟康唑耐药方面具有潜在的临床应用价值。因此，OSI作为具有共靶向活性的双重作用抗真菌剂的鉴定提出了治疗危及生命的真菌感染和克服抗真菌耐药性的潜在有效的治疗策略。
Fungal infection threatens human health worldwide due to the limited arsenal of antifungals and the rapid emergence of resistance. Epidermal growth factor receptor (EGFR) is demonstrated to mediate epithelial cell endocytosis of the leading human fungal pathogen,Candida albicans. However, whether EGFR inhibitors act on fungal cells remains unknown. Here, we discovered that the specific EGFR inhibitor osimertinib mesylate (OSI) potentiates azole efficacy against diverse fungal pathogens and overcomes azole resistance. Mechanistic investigation revealed a conserved activity of OSI by promoting intracellular fluconazole accumulation via inhibiting Pdr5 and disrupting V-ATPase function via targeting Vma1 at serine 274, eventually leading to inactivation of the global regulator TOR. Evaluation of thein vivoefficacy and toxicity of OSI demonstrated its potential clinical application in impeding fluconazole resistance. Thus, the identification of OSI as a dual action antifungal with co-targeting activity proposes a potentially effective therapeutic strategy to treat life-threatening fungal infection and overcome antifungal resistance.