Zattoni Jacopo, Ludueña Richard F, Aminpour Maral, Tuszynski Jack A
Department of Biomedical Engineering, University of Alberta, Donadeo Innovation Centre for Engineering, Edmonton, Alberta, Canada.
University of Texas Health Sciences Center, San Antonio, Texas, United States of America.
PLoS One. 2025 Jul 11;20(7):e0327621. doi: 10.1371/journal.pone.0327621. eCollection 2025.
Naegleria fowleri is a human and animal pathogen well-known for its ability to digest neurons and astrocytes of the host's brain, causing a haemorrhagic and necrotizing inflammation called Primary Amoebic Meningoencephalitis. Although infections are rare, the mortality rate is over 97%, due to both the non-specificity of the symptoms and the absence of an effective treatment. In this work we employed bioinformatics tools to evaluate the possibility of treating the infection with tubulin-targeting compounds, which we regard as the most promising approach given the unclear view on the pathogenic factors in N. fowleri, the divergence of the amoeba's tubulins from the human counterparts, and how well-established microtubule-targeting therapies are in clinical practices. The amoeba's tubulin sequences were analyzed and compared to the human tubulins to conjecture the role of their differences in drugs resistance. The binding affinity of the compounds was computed for both species by performing docking simulations using Chemical Computing Group's MOE and CCSB's AutoDock4 and AutoDock Vina. The results were analyzed using a consensus method to increase their reliability. We found that the amoeba's mitotic tubulins show a significant number of changes that are expected to decrease their affinity for tubulin-targeting compounds. We identified the Colchicine binding site as the most suitable target, and propose that Colchicine analogs retain their ability to bind to the amoeba's tubulins in vivo. The selectivity of the compounds for the pathogen however remains an issue. The changes in the amino. acid sequences in the Colchicine site could create a template for designing novel derivatives with an improved selectivity for the parasite and a safer profile for the patient. We therefore believe that our results could be the starting point for a rational derivatization of the selected ligands, leading to the development of an effective treatment for Naegleria fowleri infection.
福氏耐格里阿米巴是一种人和动物病原体，以其能够消化宿主大脑中的神经元和星形胶质细胞而闻名，会引发一种称为原发性阿米巴脑膜脑炎的出血性坏死性炎症。尽管感染罕见，但由于症状不具特异性且缺乏有效治疗方法，死亡率超过97%。在这项工作中，我们运用生物信息学工具来评估用微管蛋白靶向化合物治疗该感染的可能性。鉴于福氏耐格里阿米巴致病因素尚不明确、该变形虫的微管蛋白与人的微管蛋白存在差异，以及微管靶向疗法在临床实践中已相当成熟，我们认为这是最具前景的方法。分析了该变形虫的微管蛋白序列并与人类微管蛋白进行比较，以推测它们的差异在耐药性方面所起的作用。通过使用化学计算集团的MOE以及CCSB的AutoDock4和AutoDock Vina进行对接模拟，计算了这些化合物对两种物种的结合亲和力。使用一种共识方法分析结果以提高其可靠性。我们发现该变形虫的有丝分裂微管蛋白有大量变化，预计这些变化会降低它们对微管蛋白靶向化合物的亲和力。我们确定秋水仙碱结合位点是最合适的靶点，并提出秋水仙碱类似物在体内仍能与该变形虫的微管蛋白结合。然而，这些化合物对病原体的选择性仍是一个问题。秋水仙碱位点氨基酸序列的变化可为设计对寄生虫具有更高选择性且对患者更安全的新型衍生物创造一个模板。因此，我们相信我们的结果可能是对所选配体进行合理衍生化的起点，从而开发出一种有效的福氏耐格里阿米巴感染治疗方法。
