Identification of Off-Patent Drugs That Show Synergism with Amphotericin B or That Present Antifungal Action against Cryptococcus neoformans and Candida spp.

Author(s)

Andreia Rossi, Suelen ^{[1, 2]} ; Cesar de Oliveira, Haroldo ^{[1, 3, 4]} ; Agreda-Mellon, Daniel ^[1] ; Lucio, Jose ^[1] ; Soares Mendes-Giannini, Maria Jose ^[4] ; Pablo Garcia-Cambero, Jesus ^{[5, 6]} ; Zaragoza, Oscar ^[1]

Affiliation

^[1] Inst Salud Carlos III, Natl Ctr Microbiol, Mycol Reference Lab, Madrid - Spain

^[2] Univ Sao Paulo, ICBII, Sao Paulo - Brazil

^[3] Fundacao Oswaldo Cruz FIOCRUZ, Inst Carlos Chagas, Curitiba, Parana - Brazil

^[4] Univ Estadual Paulista, UNESP, Fac Ciencias Farmaceut, Dept Anal Clin, Campus Araraquara, Araraquara, SP - Brazil

^[5] Inst Salud Carlos III, Natl Ctr Environm Hlth, Toxicol Area, Madrid - Spain

^[6] Spanish Agcy Med & Med Devices, Dept Med Human Use, Madrid - Spain

• Document type: Journal article
• Source: Antimicrobial Agents and Chemotherapy; v. 64, n. 4 APR 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 16/20631-3 - The host immune response to anti-adhesive peptides treatment and morphological changes during infection of pathogenic fungi
• Grantee: Haroldo Cesar de Oliveira
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor