Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
Oryn Therapeutics, Vacaville, California, United States of America.
Sci Rep. 2019 Nov 15;9(1):16905. doi: 10.1038/s41598-019-53402-z.
Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.
侵袭性念珠菌病是住院和免疫抑制患者中严重且常致命感染的日益常见的原因。由于耐多药（MDR）白念珠菌和其他念珠菌属菌株的出现，这些感染的死亡率急剧上升，这凸显了新抗真菌疗法的迫切需求。恒河猴θ防御素-1（RTD-1）是一种天然的大环抗菌肽，最近被证明对体外耐多药白念珠菌的临床分离株具有快速杀菌作用。在这里，我们发现 RTD-1 对氟康唑/卡泊芬净耐药的白念珠菌菌株的芽生孢子具有快速杀菌作用，并在体外对已建立的白念珠菌生物膜具有活性。在体内，在感染时或感染后 24 小时开始全身性给予 RTD-1，无论是感染敏感株还是 MDR 株的白念珠菌，均可促进念珠菌血症小鼠的长期存活。RTD-1 在未感染和感染的小鼠中诱导早期（治疗后 4 小时）中性粒细胞增加。体内疗效与真菌清除、恢复失调的炎症细胞因子（包括 TNF-α、IL-1β、IL-6、IL-10 和 IL-17）以及循环中性粒细胞和单核细胞数量的稳态减少有关。因为这些作用是在用肽剂量产生的最高血浆浓度（Cmax）低于在 50%小鼠血清中进行体外抗真菌活性所需的 RTD-1 水平的 1%以下时发生的，同时诱导短暂的中性粒细胞增多，因此我们认为 RTD-1 通过宿主定向机制而不是直接杀菌活性在体内发挥其抗真菌作用。这项研究的结果表明，θ-防御素代表了一类用于治疗播散性念珠菌病的新型宿主定向化合物。
