PDF(Pubmed)
Abstract：
Considering the toxicity of conventional therapeutic approaches and the importance of precise mechanistic targets, it is important to explore signaling pathways implicated in fungal pathobiology. Moreover, treatment of paracoccidioidomycosis, a systemic mycosis caused by a dimorphic fungus, requires prolonged therapeutic regimens. Among the numerous factors underpinning the establishment of Paracoccidioides spp. infection, the capacity to transition from the mycelial to the yeast form is of pivotal importance. The Drk1 protein of Paracoccidioides brasiliensis likely plays a decisive role in this morphological shift and subsequent virulence. We identified peptides with affinity for the PbDrk1 protein using the phage-display method and assessed the effects of these peptides on P. brasiliensis. The peptides were found to inhibit the phase transition of P. brasiliensis. Furthermore, a substantial proportion of these peptides prevented adhesion to pneumocytes. Although these peptides may not possess inherent antifungal properties, they can augment the effects of certain antifungal agents. Notably, the cell wall architecture of P. brasiliensis appears to be modulated by peptide intervention, resulting in a reduced abundance of glycosylated proteins and lipids. These peptides were also evaluated for their efficacy in a Galleria mellonella model and shown to contribute to enhanced larval survival rates. The role of PbDrk1, which is notably absent in mammals, should be further investigated to improve the understanding of its functional role in P. brasiliensis, which may be helpful for designing novel therapeutic modalities.
摘要：
考虑到常规治疗方法的毒性和精确机制目标的重要性，探索与真菌病理生物学相关的信号通路很重要。此外，副孢子菌病的治疗，由双态真菌引起的全身性真菌病，需要长期的治疗方案。在支持副球菌属建立的众多因素中。感染,从菌丝体过渡到酵母形式的能力至关重要。巴西副球菌的Drk1蛋白可能在这种形态转变和随后的毒力中起决定性作用。我们使用噬菌体展示方法鉴定了对PbDrk1蛋白具有亲和力的肽，并评估了这些肽对巴西假单胞菌的影响。发现该肽抑制巴西假单胞菌的相变。此外，相当大比例的这些肽阻止粘附到肺细胞。虽然这些肽可能不具有固有的抗真菌特性，它们可以增强某些抗真菌药物的作用。值得注意的是,巴西芽孢杆菌的细胞壁结构似乎受到肽干预的调节，导致糖基化蛋白质和脂质的丰度降低。还评估了这些肽在Galleriamellonella模型中的功效，并显示出有助于提高幼虫存活率。PbDrk1的作用在哺乳动物中明显不存在，应进一步研究，以提高对其在巴西假单胞菌中的功能作用的认识，这可能有助于设计新的治疗方式。
