Author(s):
Rossi, Suélen Andreia ; De Oliveira, Haroldo Cesar [UNESP] ; Agreda-Mellon, Daniel ; Lucio, José ; Soares Mendes-Giannini, Maria José [UNESP] ; García-Cambero, Jesús Pablo ; Zaragoza, Oscar
Date: 2020
Persistent ID: http://hdl.handle.net/11449/200209
Origin: Oasisbr
Subject(s): Amphotericin B; Candida; Cryptococcus neoformans; Drug repurposing; Synergism; Amphotericin B; Amphotericin B; Candida; Candida; Cryptococcus neoformans; Cryptococcus neoformans; Drug repurposing; Drug repurposing; Synergism; Synergism
Description
Made available in DSpace on 2020-12-12T02:00:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Ministerio de Economía, Industria y Competitividad, Gobierno de España
Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again, its price is a limitation for its use in many regions. In the present work, we aimed to identify new drugs that have a minor effect on Cryptococcus neoformans, reducing its growth in the presence of subinhibitory concentrations of AmB. In the initial screening, we found fourteen drugs that had this pattern. Later, checkerboard assays of selected compounds, such as erythromycin, riluzole, nortriptyline, chenodiol, nisoldipine, promazine, chlorcyclizine, cloperastine, and glimepiride, were performed and all of them confirmed for their synergistic effect (fractional inhibitory concentration index [FICI] < 0.5). Additionally, toxicity of these drugs in combination with AmB was tested in mammalian cells and in zebrafish embryos. Harmless compounds, such as the antibiotic erythromycin, were found to have synergic activity with AmB, not only against C. neoformans but also against some Candida spp., in particular against Candida albicans. In parallel, we identified drugs that had antifungal activity against C. neoformans and found 43 drugs that completely inhibited the growth of this fungus, such as ciclopirox and auranofin. Our results expand our knowledge about antifungal compounds and open new perspectives in the treatment of invasive mycosis based on repurposing off-patent drugs.
Mycology Reference Laboratory National Centre for Microbiology Instituto de Salud Carlos III
Universidade Estadual Paulista (UNESP) Faculdade de Ciências Farmacêuticas Câmpus Araraquara Departamento de Análises Clínicas
Toxicology Area National Centre for Environmental Health Instituto de Salud Carlos III
Universidade de São Paulo (USP) Instituto de Ciências Biomédicas II (ICBII)
Instituto Carlos Chagas Fundação Oswaldo Cruz (Fiocruz)
Department of Medicines for Human Use Spanish Agency of Medicines and Medical Devices
Universidade Estadual Paulista (UNESP) Faculdade de Ciências Farmacêuticas Câmpus Araraquara Departamento de Análises Clínicas
FAPESP: 2016/20631-3
CNPq: 202436/2015-2
Ministerio de Economía, Industria y Competitividad, Gobierno de España: SAF2014-54336-R
Ministerio de Economía, Industria y Competitividad, Gobierno de España: SAF2017-86192-R
