Almeida Marcos Abreu, Bernardes-Engemann Andrea Reis, Coelho Rowena Alves, Lugones Camila Jantoro Guzman, de Andrade Iara Bastos, Corrêa-Junior Dario, de Oliveira Simone Santiago Carvalho, Dos Santos André Luis Souza, Frases Susana, Rodrigues Márcio Lourenço, Valente Richard Hemmi, Zancopé-Oliveira Rosely Maria, Almeida-Paes Rodrigo
Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro 21040-900, Brazil.
Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
J Fungi (Basel). 2023 Mar 21;9(3):385. doi: 10.3390/jof9030385.
Histoplasmosis is a frequent mycosis in people living with HIV/AIDS and other immunocompromised hosts. Histoplasmosis has high rates of mortality in these patients if treatment is unsuccessful. Itraconazole and amphotericin B are used to treat histoplasmosis; however, both antifungals have potentially severe pharmacokinetic drug interactions and toxicity. The present study determined the minimal inhibitory and fungicidal concentrations of mebendazole, a drug present in the NIH Clinical Collection, to establish whether it has fungicidal or fungistatic activity against . Protein extracts from yeasts, treated or not with mebendazole, were analyzed by proteomics to understand the metabolic changes driven by this benzimidazole. Mebendazole inhibited the growth of 10 strains, presenting minimal inhibitory concentrations ranging from 5.0 to 0.08 µM. Proteomics revealed 30 and 18 proteins exclusively detected in untreated and mebendazole-treated yeast cells, respectively. Proteins related to the tricarboxylic acid cycle, cytoskeleton, and ribosomes were highly abundant in untreated cells. Proteins related to the nitrogen, sulfur, and pyrimidine metabolisms were enriched in mebendazole-treated cells. Furthermore, mebendazole was able to inhibit the oxidative metabolism, disrupt the cytoskeleton, and decrease ribosomal proteins in . These results suggest mebendazole as a drug to be repurposed for histoplasmosis treatment.
组织胞浆菌病在人类免疫缺陷病毒/艾滋病患者及其他免疫功能低下宿主中是一种常见的真菌病。如果治疗不成功，组织胞浆菌病在这些患者中的死亡率很高。伊曲康唑和两性霉素B用于治疗组织胞浆菌病；然而，这两种抗真菌药物都有潜在的严重药代动力学药物相互作用和毒性。本研究确定了美国国立卫生研究院临床收藏中的一种药物甲苯达唑的最小抑菌浓度和杀菌浓度，以确定它是否对[此处原文缺失相关真菌名称]具有杀菌或抑菌活性。通过蛋白质组学分析了用甲苯达唑处理或未处理的酵母的蛋白质提取物，以了解这种苯并咪唑驱动的代谢变化。甲苯达唑抑制了10株[此处原文缺失相关真菌名称]菌株的生长，其最小抑菌浓度范围为5.0至0.08µM。蛋白质组学分别揭示了在未处理和甲苯达唑处理的酵母细胞中仅检测到的30种和18种蛋白质。与三羧酸循环、细胞骨架和核糖体相关的蛋白质在未处理的细胞中高度丰富。与氮、硫和嘧啶代谢相关的蛋白质在甲苯达唑处理过的细胞中富集。此外，甲苯达唑能够抑制[此处原文缺失相关真菌名称]的氧化代谢、破坏细胞骨架并减少核糖体蛋白。这些结果表明甲苯达唑可作为一种重新用于治疗组织胞浆菌病的药物。
