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Synth Syst Biotechnol. 2016 Oct 25;1(3):158-168. doi: 10.1016/j.synbio.2016.10.001. eCollection 2016 Sep.

Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters.

Author information

1
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
2
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby, 2800, Denmark.
3
University of Chinese Academy of Sciences, Beijing 100049, China.
4
Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510260, China.
5
Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, US.
6
Department of Immunology, School of Medicine, Tongji University, Shanghai 200092, China.
7
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
8
Institute of Health Sciences, School of Life Sciences, Anhui University, Hefei 230601, China.
9
Research Center for Tropical Diseases, Kitasato Institute for Life Sciences, Kitasato University, Tokyo 108-8641, Japan.
10
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
11
Sir John Walsh Research Institute, University of Otago, Dunedin 9016, New Zealand.
12
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.

Abstract

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 Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal activity in vitro 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 C. albicans.

KEYWORDS:

ABC transporter; Beauvericin; Candida albicans; Multi-drug resistance; Synergy; Virtual screening

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