Antifungal activity and mode of action of synthetic peptides derived from the tick OsDef2 defensin,Journal of Peptide Science

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Antifungal activity and mode of action of synthetic peptides derived from the tick OsDef2 defensin
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2021-12-05 , DOI: 10.1002/psc.3383
Kabuzi R Mbuayama ₁ , Helena Taute ₂ , Adam A Strӧmstedt ₃ , Megan J Bester ₂ , Anabella R M Gaspar ₁

Affiliation

Candida albicans is the principal opportunistic fungal pathogen in nosocomial settings and resistance to antifungal drugs is on the rise. Antimicrobial peptides from natural sources are promising novel therapeutics against C. albicans. OsDef2 defensin was previously found to be active against only Gram-positive bacteria, whereas derived fragments Os and its cysteine-free analogue, Os-C, are active against Gram-positive and Gram-negative bacteria at low micromolar concentrations. In this study, OsDef2-derived analogues and fragments were screened for anticandidal activity with the aim to identify peptides with antifungal activity and in so doing obtain a better understanding of the structural requirements for activity and modes of action. Os, Os-C and Os(11–22)NH₂, a Os-truncated carboxy-terminal-amidated fragment, had the most significant antifungal activities, with minimum fungicidal concentrations (MFCs) in the micromolar range (6–28 μM). C. albicans killing was rapid and occurred within 30–60 min. Further investigations showed all three peptides interacted with cell wall derived polysaccharides while both Os and Os(11–22)NH₂ permeabilized fungal liposomes. Confocal laser scanning microscopy confirmed that Os-C and Os(11–22)NH₂ could enter the cytosol of live cells and subsequent findings suggest that the uptake of Os and Os-C, in contrast to Os(11–22)NH₂, is energy dependent. Although Os, Os-C and Os(11–22)NH₂ induced the production of reactive oxygen species (ROS), co-incubation with ascorbic acid revealed that only ROS generated by Os-C and to a lesser extent Os(11–22)NH₂ resulted in cell death. Overall, Os, Os-C and Os(11–22)NH₂ are promising candidacidal agents.

中文翻译：

来自蜱 OsDef2 防御素的合成肽的抗真菌活性和作用方式

白色念珠菌是医院环境中主要的机会性真菌病原体，并且对抗真菌药物的耐药性正在上升。来自天然来源的抗菌肽是有希望的针对白色念珠菌的新疗法。OsDef2 防御素之前被发现仅对革兰氏阳性菌有活性，而衍生片段 Os 及其不含半胱氨酸的类似物 Os-C 在低微摩尔浓度下对革兰氏阳性和革兰氏阴性菌有活性。在这项研究中，筛选了 OsDef2 衍生的类似物和片段的抗念珠菌活性，目的是鉴定具有抗真菌活性的肽，从而更好地了解活性和作用模式的结构要求。Os、Os-C 和 Os(11–22)NH ₂是一种截短的羧基末端酰胺化片段，具有最显着的抗真菌活性，最低杀菌浓度 (MFC) 在微摩尔范围内 (6–28 μM)。白色念珠菌的杀灭速度很快，发生在 30-60 分钟内。进一步的研究表明，所有三种肽都与细胞壁衍生的多糖相互作用，而 Os 和 Os(11-22)NH ₂都可渗透真菌脂质体。共聚焦激光扫描显微镜证实 Os-C 和 Os(11-22)NH ₂可以进入活细胞的胞质溶胶，随后的研究结果表明，与 Os(11-22)NH ₂相比，Os 和 Os-C 的吸收, 是能量依赖的。虽然 Os、Os-C 和 Os(11-22)NH ₂诱导活性氧（ROS）的产生，与抗坏血酸共孵育表明只有Os-C产生的ROS和较小程度的Os（11-22）NH ₂导致细胞死亡。总体而言，Os、Os-C 和 Os(11–22)NH ₂是有希望的候选药物。

更新日期：2022-02-10

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