Kalopanaxsaponin A induces reactive oxygen species mediated mitochondrial dysfunction and cell membrane destruction in Candida albicans.

Ying Li,Zuobin Zhu,Yao Zhu,Hongchun Li,Bing Gu,Huankai Yao,Mingzhu Shan,Roy Aziz Khalaf

doi:10.1371/journal.pone.0243066

Abstract

Candidiasis causes high morbidity and mortality among immunocompromised patients. Antifungal drug resistance and cytotoxicity highlight the need of effective antifungal therapeutics. In this study, we found that kalopanaxsaponin A (KPA), a triterpenoid saponin natural product, could inhibit the proliferation of various Candida species, and exerted a fungicidal effect against C. albicans. To further explore its antifungal action mode, spectrofluorophotometer, fluorescence microscopy and transmission electron microscopy were performed, showing that KPA treatment induced the accumulation of intracellular reactive oxygen species (ROS), resulting in mitochondrial dysfunction. Meanwhile, KPA treatment also broke down the membrane barrier of C. albicans causing the leakage of intracellular trehalose, the entrance of extracellular impermeable substance and the decrease of ergosterol content. Both ROS accumulation and membrane destruction contributed to the death of C. albicans cells. Our work preliminarily elucidated the potential mechanisms of KPA against C. albicans on a cellular level, and might provide a potential option for the treatment of clinical candidiasis.

Highlights

Candida albicans is the major pathogenic source of candidiasis worldwide accompanying with other non-albicans Candida species, including C. glabrata, C. parapsilosis, C. tropicalis and C. krusei [1,2]
The results showed that kalopanaxsaponin A (KPA) exerted a moderate antifungal effect against the five most common Candida species, including C. albicans, C. glabrata, C. parapsilosis, C. tropicalis and C. krusei, the MIC80 value of which was all 16 μg/mL
After 12 h treatment, put cells back to fresh media, both KPA and Amphotericin B (AMB) treated cells did not revive until 48 h. These results implied that KPA exerted a fungicidal effect against C. albicans and could inhibit its proliferation in two hours

Summary

Introduction

Candida albicans is the major pathogenic source of candidiasis worldwide accompanying with other non-albicans Candida species, including C. glabrata, C. parapsilosis, C. tropicalis and C. krusei [1,2]. Invasive candidiasis is closely linked to the advanced medical technology and has high morbidity and mortality (~ 40%) in nosocomial. Even with the treatment of the antifungal agents available, by far, candidiasis remains the most common fungal infection disease, ranking the third-to-fourth most frequent nosocomial infections in the United States [4]. Long-term antifungal therapy and biofilms formed on both biological and inert surfaces accelerate the development of drug resistance, complicating the management of candidiasis [5,6]. Resistance and cytotoxicity are the inevitable problems for most antifungal drugs [7,8]. Novel antifungal drugs or therapeutic strategies are urgently need for the clinical treatment of candidiasis

Methods

Results

Conclusion