Mebendazole Inhibits Histoplasma capsulatum In Vitro Growth and Decreases Mitochondrion and Cytoskeleton Protein Levels

• Published in: Journal of fungi (Basel) 2023-03, Vol.9 (3), p.385
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Amphotericin B; antifungal activity; benzimidazole; Benzimidazoles; Cytoskeleton; Drug interactions; drug repurposing; Drug resistance; Histoplasma capsulatum; Histoplasmosis; HIV; Human immunodeficiency virus; Immunocompromised hosts; Infections; Itraconazole; Mebendazole; Metabolism; Mortality; Mycosis; Oxidative metabolism; Pharmacokinetics; Proteins; Proteomics; Ribosomal proteins; Ribosomes; Toxicity; Tricarboxylic acid cycle; Viral infections
• ISSN: 2309-608X; 2309-608X
• 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.