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New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis.
Future Microbiol 2019; 14:969-980FM

Abstract

Aim:

A structural model of chorismate synthase (CS) from the pathogenic fungus Candida albicans was used for virtual screening simulations.

Methods:

Docking, molecular dynamics, cell growth inhibition and protein binding assays were used for search and validation.

Results:

Two molecules termed CS8 and CaCS02 were identified. Further studies of the minimal inhibitory concentration demonstrated fungicidal activity against Paracoccidioides brasiliensis with a minimal inhibitory concentration and minimal fungicidal concentration of 512 and 32 μg·ml-1 for CS8 and CaCS02, respectively. In addition, CaCS02 showed a strong synergistic effect in combination with amphotericin B without cytotoxic effects. In vitro studies using recombinant CS from P. brasiliensis showed IC50 of 29 μM for CaCS02 supporting our interpretation that inhibition of CS causes the observed fungicidal activity.

Authors+Show Affiliations

Department of Technology, Universidade Estadual de Maringá, Av. Ângelo Moreira da Fonseca, 1800, 87506-370 Umuarama, PR, Brazil.Department of Clinical Analysis & Biomedicine, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá, PR, Brazil.Institute of Biochemistry, Graz University of Technology, Petersgasse 12/2, 8010, Graz, Austria.Institute of Biochemistry, Graz University of Technology, Petersgasse 12/2, 8010, Graz, Austria.Department of Clinical Analysis & Biomedicine, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá, PR, Brazil.Department of Technology, Universidade Estadual de Maringá, Av. Ângelo Moreira da Fonseca, 1800, 87506-370 Umuarama, PR, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31382783

Citation

Bueno, Paulo Sa, et al. "New Inhibitors of Chorismate Synthase Present Antifungal Activity Against Paracoccidioides Brasiliensis." Future Microbiology, vol. 14, 2019, pp. 969-980.
Bueno PS, Rodrigues-Vendramini FA, Toplak M, et al. New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis. Future Microbiol. 2019;14:969-980.
Bueno, P. S., Rodrigues-Vendramini, F. A., Toplak, M., Macheroux, P., Kioshima, É. S., & Seixas, F. A. (2019). New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis. Future Microbiology, 14, pp. 969-980. doi:10.2217/fmb-2019-0052.
Bueno PS, et al. New Inhibitors of Chorismate Synthase Present Antifungal Activity Against Paracoccidioides Brasiliensis. Future Microbiol. 2019;14:969-980. PubMed PMID: 31382783.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis. AU - Bueno,Paulo Sa, AU - Rodrigues-Vendramini,Franciele Av, AU - Toplak,Marina, AU - Macheroux,Peter, AU - Kioshima,Érika S, AU - Seixas,Flavio Av, Y1 - 2019/08/06/ PY - 2019/8/7/pubmed PY - 2019/8/7/medline PY - 2019/8/7/entrez KW - antifungal KW - chorismate synthase KW - inhibitor KW - paracoccidioidomycosis KW - systemic mycosis SP - 969 EP - 980 JF - Future microbiology JO - Future Microbiol VL - 14 N2 - Aim: A structural model of chorismate synthase (CS) from the pathogenic fungus Candida albicans was used for virtual screening simulations. Methods: Docking, molecular dynamics, cell growth inhibition and protein binding assays were used for search and validation. Results: Two molecules termed CS8 and CaCS02 were identified. Further studies of the minimal inhibitory concentration demonstrated fungicidal activity against Paracoccidioides brasiliensis with a minimal inhibitory concentration and minimal fungicidal concentration of 512 and 32 μg·ml-1 for CS8 and CaCS02, respectively. In addition, CaCS02 showed a strong synergistic effect in combination with amphotericin B without cytotoxic effects. In vitro studies using recombinant CS from P. brasiliensis showed IC50 of 29 μM for CaCS02 supporting our interpretation that inhibition of CS causes the observed fungicidal activity. SN - 1746-0921 UR - https://www.unboundmedicine.com/medline/citation/31382783/New_inhibitors_of_chorismate_synthase_present_antifungal_activity_against_Paracoccidioides_brasiliensis L2 - http://www.futuremedicine.com/doi/full/10.2217/fmb-2019-0052?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -