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

Yaojun Tong, Mei Liu, Yu Zhang, Xueting Liu, Ren Huang, Fuhang Song, Huanqin Dai, Biao Ren, Nuo Sun, Gang Pei, Jiang Bian, Xin-Ming Jia, Guanghua Huang, Xuyu Zhou, Shaojie Li, Buchang Zhang, Takashi Fukuda, Hiroshi Tomoda, Satoshi Ōmura, Richard D. CannonRichard Calderone, Lixin Zhang

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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.
Original languageEnglish
JournalSynthetic and Systems Biotechnology
Volume1
Issue number3
Pages (from-to)158-168
Number of pages11
ISSN2405-805x
DOIs
Publication statusPublished - 2016

Keywords

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

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