A semisynthetic borrelidin analogue BN-3b exerts potent antifungal activity against Candida albicans through ROS-mediated oxidative damage

Peipei Guan,Yu Mu,Xiaodan Qu,Li Han,Xueshi Huang,Hao Su,Bixuan Cao,Caijuan Hu

doi:10.1038/s41598-020-61681-0

Peipei Guan, Yu Mu + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-61681-0

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Journal: Scientific Reports	Publication Date: Mar 19, 2020
Citations: 8	License type: open-access

Affiliation: Northeastern University

Abstract

In the process of investigating the antifungal structure-activity relationships (SAR) of borrelidin and discovering antifungal leads, a semisynthetic borrelidin analogue, BN-3b with antifungal activity against Candida albicans, was achieved. In this study, we found that oxidative damage induced by endogenous reactive oxygen species (ROS) plays an important role in the antifungal activity of BN-3b. Further investigation indicated that BN-3b stimulated ROS accumulation, increased malondialdehyde (MDA) levels, and decreased reduced/oxidized glutathione (GSH/GSSG) ratio. Moreover, BN-3b decreased mitochondrial membrane potential (MMP) and ATP generation. Ultrastructure analysis revealed that BN-3b severely damaged the cell membrane of C. albicans. Quantitative PCR (RT-qPCR) analysis revealed that virulence factors of C. albicans SAPs, PLB1, PLB2, HWP1, ALSs, and LIPs were all down-regulated after BN-3b exposure. We also found that BN-3b markedly inhibited the hyphal formation of C. albicans. In addition, in vivo studies revealed that BN-3b significantly prolonged survival and decreased fungal burden in mouse model of disseminated candidiasis.

Highlights

In the process of investigating the antifungal structure-activity relationships (SAR) of borrelidin and discovering antifungal leads, a semisynthetic borrelidin analogue, borrelidin derivatives (BNs)-3b with antifungal activity against Candida albicans, was achieved
The results indicated treatment with BN-3b at 0.5 × MIC reduced the cell viability of C. albicans SC5314 even after 2 h of treatment compared with the vehicle group; treatment with BN-3b at MIC and 1.5 × MIC exhibited fungicidal activity against C. albicans SC5314 in a dose and time-dependent manner within 8 h; BN-3b at higher concentrations (2 × MIC and 3 × MIC) decreased yeast viability in a time-dependent manner even after 8 h (Fig. 1B)
We evaluated the in vivo antifungal activity of BN-3b by establishing the systemic mouse model of disseminated candidiasis

Summary

Introduction

In the process of investigating the antifungal structure-activity relationships (SAR) of borrelidin and discovering antifungal leads, a semisynthetic borrelidin analogue, BN-3b with antifungal activity against Candida albicans, was achieved. Several studies have suggested that endogenous ROS mediated oxidative damage participate in the antifungal activity of amphotericin B (AMB) and fluconazole (FLC)[7,8,9,10,11]. These findings implied that oxidative stress involved in the antifungal mechanism of antifungal agents. C. albicans has developed an effective battery of virulence factors[13] that promote disease establishment and progression[14] Among these virulence factors, lipases (LIPs), phospholipases, agglutinin-like sequences (ALSs), secreted aspartyl proteinases (SAPs), and hyphal wall protein (HWP1) are most significant in virulence[14,15,16,17]. We determined the expression of virulence factors (SAPs, PLB1, PLB2, HWP1, ALSs, and LIPs) of C. albicans after exposure to BN-3b using RT-qPCR

Methods

Results

Conclusion