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ANTIFUNGAL ACTIVITY OF ACYLHYDRAZONE DERIVATIVES AGAINST SPOROTHRIX SPP
Bonilla, Jhon Jhamilton Artunduaga et al. | Date Issued: 2021
Author
Bonilla, Jhon Jhamilton Artunduaga
Honorato, Leandro
Haranahalli, Krupanandan
Gremião, Isabella Dib Ferreira
Pereira, Sandro Antonio
Guimarães, Allan
Baptista, Andrea Regina de Souza
Tavares, Patricia de M.
Rodrigues, Marcio L.
Miranda, Kildare
Ojima, Iwao
Poeta, Maurizio Del
Nimrichter, Leonardo
Affilliation
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Glicobiologia de Eucariotos. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Glicobiologia de Eucariotos. Rio de Janeiro, RJ, Brasil.
Stony Brook University. Institute of Chemical Biology and Drug Discovery. Stony Brook, NY, USA / Stony Brook University. Department of Chemistry. Stony Brook, NY, USA.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em Dermatozoonoses em Animais Domésticos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em Dermatozoonoses em Animais Domésticos. Rio de Janeiro, RJ, Brasil.
Universidade Federal Fluminense. Departamento de Microbiologia e Parasitologia. Laboratório de Bioquímica e Imunologia das Micoses. Niterói, RJ, Brasil.
Universidade Federal Fluminense. Centro de Investigação de Microrganismos. Niterói, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Glicobiologia de Eucariotos. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Rio de Janeiro, RJ, Brasil.
Instituto de Biofísica Carlos Chagas Filho. Laboratório de Ultraestrutura Celular Hertha Meyer. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Centro Nacional de Biologia Estrutural e Bioimagem. Rio de Janeiro, RJ, Brasil.
Stony Brook University. Institute of Chemical Biology and Drug Discovery. Stony Brook, NY, USA / Stony Brook University. Department of Chemistry. Stony Brook, NY, USA.
Stony Brook University. Institute of Chemical Biology and Drug Discovery. Stony Brook, NY, USA / Stony Brook University. Department of Microbiology and Immunology. Stony Brook, NY, USA / Stony Brook University. School of Medicine. Division of Infectious Diseases. Stony Brook, NY, USA / Veterans Administration Medical Center. Northport, NY, USA.
Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de Góes. Departamento de Microbiologia Geral. Laboratório de Glicobiologia de Eucariotos. Rio de Janeiro, RJ, Brasil.
Abstract
Sporotrichosis is an emerging mycosis caused by members of the genus Sporothrix The disease affects humans and animals, particularly cats, which plays an important role in the zoonotic transmission. Feline sporotrichosis treatment options include itraconazole (ITC), potassium iodide and amphotericin B, drugs usually associated with deleterious adverse reactions and refractoriness in cats, especially when using ITC. Thus, affordable, non-toxic and clinically effective anti-Sporothrix agents are needed. Recently, acylhydrazones (AH), molecules targeting vesicular transport and cell cycle progression, exhibited a potent antifungal activity against several fungal species and displayed low toxicity when compared to the current drugs. In this work, the AH derivatives D13 and SB-AF-1002 were tested against Sporothrix schenckii and Sporothrix brasiliensis Minimal inhibitory concentrations of 0.12 - 1 μg/mL were observed for both species in vitro D13 and SB-AF-1002 showed an additive effect with itraconazole. Treatment with D13 promoted yeast disruption with release of intracellular components, as confirmed by transmission electron microscopy of S. brasiliensis exposed to the AH derivatives. AH-treated cells displayed thickening of the cell wall, discontinuity of the cell membrane and an intense cytoplasmic degeneration. In a murine model of sporotrichosis, treatment with AH derivatives was more efficient than ITC, the drug of choice for sporotrichosis. The results of the preliminary clinical study in cats indicate that D13 is safe and has potential to become a therapeutic option for sporotrichosis when associated to ITC. Our results expand the antifungal broadness of AH derivatives and suggest that these drugs could be exploited to combat sporotrichosis.
Keywords
Acylhydrazone derivatives
Sporothrix brasiliensis
Sporothrix schenckii
Cutaneous sporotrichosis
Antifungals
Mice
 
Publisher
American Society for Microbiology
Citation
BONILLA, Jhon Jhamilto Artunduaga et al. Antifungal activity of Acylhydrazone derivatives against Sporothrix spp. Antimicrobial Agents and chemotherapy, v. 65, n. 5, p. 1-11, 2021.
DOI
10.1128/AAC.02593-20
ISSN
0066-4804