Tong Yaojun, Liu Mei, Zhang Yu, Liu Xueting, Huang Ren, Song Fuhang, Dai Huanqin, Ren Biao, Sun Nuo, Pei Gang, Bian Jiang, Jia Xin-Ming, Huang Guanghua, Zhou Xuyu, Li Shaojie, Zhang Buchang, Fukuda Takashi, Tomoda Hiroshi, Ōmura Satoshi, Cannon Richard D, Calderone Richard, Zhang Lixin
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby, 2800, Denmark.
Synth Syst Biotechnol. 2016 Oct 25;1(3):158-168. doi: 10.1016/j.synbio.2016.10.001. eCollection 2016 Sep.
Multi-drug resistance of pathogenic microorganisms is becoming a serious threat, particularly to immunocompromised populations. The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies. Unfortunately, with traditional drug discovery approaches, only echinocandins was approved by FDA as a new class of antifungals in the past two decades. Drug efflux is one of the major contributors to multi-drug resistance, the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance. In this study, we combined structure-based virtual screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal activity by elevating intracellular calcium and reactive oxygen species (ROS). It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole (KTC) and could cure the murine model of disseminated candidiasis. Toxicity evaluation of BEA, including acute toxicity test, Ames test, and hERG (human ether-à-go-go-related gene) test promised that BEA can be harnessed for treatment of candidiasis, especially the candidiasis caused by ABC overexpressed multi-drug resistant .
病原微生物的多重耐药性正成为一个严重威胁，尤其是对免疫功能低下人群。系统性真菌感染的高死亡率需要新型抗真菌药物和治疗方法。不幸的是，采用传统的药物发现方法，在过去二十年里只有棘白菌素被美国食品药品监督管理局（FDA）批准为一类新的抗真菌药物。药物外排是导致多重耐药性的主要因素之一，药物外排泵的调节剂被认为是攻克多重耐药性的关键之一。在本研究中，我们结合基于结构的虚拟筛选和基于全细胞的机制研究，鉴定出一种天然产物白僵菌素（BEA）作为药物外排泵调节剂，它可以通过特异性阻断ATP结合盒（ABC）转运蛋白来逆转多重耐药表型；同时，BEA单独使用时通过升高细胞内钙和活性氧（ROS）具有杀菌活性。组织病理学研究进一步证明，BEA与亚治疗剂量的酮康唑（KTC）协同作用，可以治愈播散性念珠菌病的小鼠模型。对BEA的毒性评估，包括急性毒性试验、艾姆斯试验和人ether-à-go-go相关基因（hERG）试验表明，BEA可用于治疗念珠菌病，尤其是由ABC过表达的多重耐药菌株引起的念珠菌病。
