Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species
Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species
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DOI：
10.1128/aac.00111-18
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发表时间：
2018-06-01
影响因子：
4.9
通讯作者：
Selsted, Michael E.
中科院分区：
文献类型：
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作者：
Basso, Virginia;Garcia, Angie;Selsted, Michael E.
系统性念珠菌病是一个日益增长的卫生保健问题，由于多药耐药（MDR）念珠菌属引起的感染频率越来越高，变得更具挑战性。因此，迫切需要新的治疗方法来治疗念珠菌病，包括由对真菌病原体的天然宿主防御的见解所启发的策略。针对白色念珠菌和非白色念珠菌的一组药物敏感和耐药临床分离株，研究了θ-防御素（旧大陆猴组织中表达的大环肽）的抗真菌特性。Rhesus theta-defensin 1（RTD-1）是Theta-防御素的原型，具有快速、有效的抗耐药和耐多药的抗真菌作用。白色念珠菌菌株。真菌的杀伤发生细胞透化，在时间上与ATP的释放和细胞内积累的活性氧（ROS）。RTD-1的杀伤作用与组胺素5（Hst 5）进行了比较，组胺素5是一种在人唾液中表达的广泛表征的抗念珠菌肽。RTD-1对C.白色念珠菌的作用更快，并且浓度比Hst 5低200倍。与Hst 5不同，RTD-1的抗Candidal活性不依赖于线粒体ATP的产生。此外，RTD-1是完全耐念珠菌蛋白酶2小时的条件下，迅速和完全降解Hst 5。14种天然防御素异构体对耐药念珠菌的MIC和最小杀菌浓度（MFC）。白色念珠菌分离物鉴定出比阿替霉素B和/或卡泊芬净对氟康唑耐药生物体（包括MDR耳念珠菌）更有活性的肽。这些结果表明大环θ-防御素作为抗真菌疗法设计结构模板的潜力。
Systemic candidiasis is a growing health care concern that is becoming even more challenging due to the growing frequency of infections caused by multidrug-resistant (MDR) Candida species. Thus, there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of theta-defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug-sensitive and drug-resistant clinical isolates of Candida albicans and non-albicans Candida species. Rhesus theta-defensin 1 (RTD-1), the prototype theta-defensin, was rapidly and potently fungicidal against drug-sensitive and MDR C. albicans strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that by histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed C. albicans much more rapidly and at a >200-fold lower concentration than that of Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to Candida proteases for 2 h under conditions that rapidly and completely degraded Hst 5. MICs and minimum fungicidal concentrations (MFCs) of 14 natural theta-defensins isoforms against drug-resistant C. albicans isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole-resistant organisms, including MDR Candida auris. These results point to the potential of macrocyclic theta-defensins as structural templates for the design of antifungal therapeutics.