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

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.

FK506 Resistance of Saccharomyces cerevisiae Pdr5 and Candida albicans Cdr1 Involves Mutations in the Transmembrane Domains and Extracellular Loops

“…These modifications make AD exquisitely sensitive to most xenobiotics, and they enable exceptionally high levels of expression of heterologous multidrug efflux pumps that can result in up to 100-to 5,000-fold increased drug resistance. The fluconazole (FLC) susceptibilities (50)(51)(52) and inhibitor sensitivities (53)(54)(55)(56) of C. albicans Cdr1 knockout strains and C. albicans clinical isolates overexpressing Cdr1 were remarkably similar to those of our azole-sensitive S. cerevisiae host strain and the azole-resistant S. cerevisiae strain overexpressing Cdr1 (18,19,55,57). This validates the functional characterization of C. albicans Cdr1 in S. cerevisiae AD despite obvious differences in lipid composition, membrane potential, and bioenergetics between these two evolutionarily distant fungal species.…”

Promising Antifungal Targets Against Candida albicans Based on Ion Homeostasis

“…Ethylenediaminetetraacetic acid (EDTA) and ethylene- bis (oxyethylenenitrilo)tetraacetic acid (EGTA) are two calcium chelators that possess antifungal activity contributing to their property of calcium chelating (Ates et al, 2005 ). Moreover, Yaojun Tong et al identified that beauvericin had fungicidal activity in vitro by elevating intracellular calcium and ROS, and the MIC 90 of beauvericin was 8 μg/mL (Tong et al, 2016 ). Particularly, mitochondrial Ca 2+ overload plays a crucial role in the process of apoptosis.…”

A Review on the Synthesis and Bioactivity Aspects of Beauvericin, a Fusarium Mycotoxin

“…Cell organelles or enzyme systems are the targets of BEA (Prince et al, 1974 ; Wang and Xu, 2012 ). Based on the antibacterial activity against plant pathogens (Xu et al, 2010 ), BEA could be utilized in the control of non-food crop diseases and to solve the problems of drug resistance (Tong et al, 2016 ).…”

“…An administration of BEA with ketoconazole shows an antifungal effect with more than 100-fold higher than that by a single application (Zhang et al, 2007 ). The mechanism of antifungal activity of BEA has been studies by numerous studies (Mei et al, 2009 ; Shekhar-Guturja et al, 2016a ; Tong et al, 2016 ). The synergetic effect is not due to their pharmacokinetic interactions (Mei et al, 2009 ).…”