ABSTRACT

The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.

摘要

近年来，真菌感染的发生率不断上升。卡泊芬净（CAS）是治疗全身性真菌感染的一线药物之一。然而，新出现的CAS耐药临床分离株和CAS给药的高经济成本阻碍了该药物的广泛应用。因此，CAS与其他化合物联合给药可增强抗真菌活性并减少CAS剂量越来越受到关注。在这项研究中，我们研究了芒果苷 (MG) 对 CAS 抗真菌活性的影响。我们的结果表明，MG 与 CAS 协同作用于多种念珠菌属，包括抗 CAS 的白色念珠菌。此外，MG 可以增强 CAS 对生物膜的活性。在体内在播散性念珠菌病小鼠模型中进一步证实了 MG 和 CAS 的协同作用。为了探索其机制，我们发现 SPE1 介导的多胺生物合成途径参与了真菌细胞对卡泊芬净的应激。CAS 单独处理可刺激 SPE1 表达和多胺的积累，而 MG 和 CAS 联合处理可抑制 SPE1 表达并破坏多胺积累，这可能有助于增加氧化损伤和细胞死亡。这些结果为高效抗真菌治疗提供了一种有前景的策略，并揭示了 CAS 抗性的新机制。