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

Abstract

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 Histoplasma capsulatum. Protein extracts from H. capsulatum 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 H. capsulatum 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 H. capsulatum 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 H. capsulatum. These results suggest mebendazole as a drug to be repurposed for histoplasmosis treatment.

Repurposing Benzimidazoles against Causative Agents of Chromoblastomycosis: Albendazole Has Superior In Vitro Activity Than Mebendazole and Thiabendazole

“…Some studies have demonstrated antifungal activity of benzimidazoles such as flubendazole [65], albendazole [66], and mebendazole [35] against Cryptococcus neoformans, fenbendazole [67] against Cryptococcus gattii and C. neoformans, albendazole against Aspergillus spp. [68], and, more recently, mebendazole against Histoplasma capsulatum [49]. Similarly, our findings demonstrated antifungal activity in a group of anthelmintic benzimidazoles against CBM agents, suggesting potential targets for the development of new broad-range antifungal drugs.…”

“…A collection of substances-NIH Clinical Collection-was used in this study to identify drugs with antifungal activity against several CBM agents, and therefore with repurposing potential for CBM. This collection has been previously tested on other fungi [35,48,49], and, as observed here, benzimidazoles were also found to have antifungal activity.…”