Kinome analysis of Madurella mycetomatis identified kinases in the cell wall integrity pathway as novel potential therapeutic drug targets in eumycetoma caused by Madurella mycetomatis.

IF 3.4 2区医学 Q1 PARASITOLOGY

PLoS Neglected Tropical Diseases Pub Date : 2025-09-04 eCollection Date: 2025-09-01 DOI:10.1371/journal.pntd.0013482

Mickey Konings, Nikolaos Strepis, Ri-Ichiroh Manabe, Akira Hasegawa, Somdatta Chaudhari, Saskia du Pré, Marij Schippers, Michihira Tagami, Jingyi Ma, Yasushi Okazaki, Matthew Todd, Bernhard Biersack, Vijay Masand, Annelies Verbon, Takeya Kasukawa, Imad Abugessaisa, Wendy W J van de Sande

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Abstract

Eumycetoma is a neglected tropical subcutaneous disease most commonly caused by the fungus Madurella mycetomatis. Currently, eumycetoma is treated by a combination of antifungal therapy and surgery, with limited success rates. To identify novel drug targets we used an in silico approach to determine the kinases present in M. mycetomatis genome and rank them as potential drug targets. In total 132 predicted kinases were identified in M. mycetomatis, of which 21 were predicted to be essential for fungal viability and 4 of these had no human orthologues. Two were linked to the Cell Wall Integrity (CWI) signalling pathway and were expressed in a Galleria mellonella infection model. Several kinase inhibitors were identified after in silico modelling, however only 8 were able to inhibit growth. Five had predicted binding affinity with components of the CWI. Altogether, the CWI shows potential as a drug target for further evaluation.

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足跖麦氏球藻的Kinome分析发现细胞壁完整性通路中的激酶是治疗足跖麦氏球藻引起的真菌性肿的新的潜在药物靶点。

足菌肿是一种被忽视的热带皮下疾病，最常见的是由真菌引起的足菌肿。目前，真菌瘤的治疗是通过抗真菌治疗和手术相结合，成功率有限。为了确定新的药物靶点，我们使用了一种计算机方法来确定存在于支原体基因组中的激酶，并将它们列为潜在的药物靶点。在真菌分枝杆菌中共鉴定出132种预测激酶，其中21种预测为真菌生存所必需，其中4种没有人类同源物。其中两个与细胞壁完整性（CWI）信号通路相关，并在mellonella感染模型中表达。在计算机模拟后，确定了几种激酶抑制剂，但只有8种能够抑制生长。其中五个预测了与CWI成分的结合亲和力。总之，CWI显示出作为进一步评估的药物靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

PLoS Neglected Tropical Diseases PARASITOLOGY-TROPICAL MEDICINE

自引率

10.50%

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723

期刊介绍： PLOS Neglected Tropical Diseases publishes research devoted to the pathology, epidemiology, prevention, treatment and control of the neglected tropical diseases (NTDs), as well as relevant public policy. The NTDs are defined as a group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of low-income and middle-income countries. Their impact on child health and development, pregnancy, and worker productivity, as well as their stigmatizing features limit economic stability. All aspects of these diseases are considered, including: Pathogenesis Clinical features Pharmacology and treatment Diagnosis Epidemiology Vector biology Vaccinology and prevention Demographic, ecological and social determinants Public health and policy aspects (including cost-effectiveness analyses).