New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis

Paulo S.A. Bueno, Franciele A.V. Rodrigues-Vendramini, Marina Toplak, Peter Macheroux, Érika S. Kioshima, Flavio A.V. Seixas*

*Korrespondierende/r Autor/in für diese Arbeit

Publikation: Beitrag in einer FachzeitschriftArtikel

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.

Originalspracheenglisch
Seiten (von - bis)969-980
Seitenumfang12
FachzeitschriftFuture Microbiology
Jahrgang14
Ausgabenummer11
DOIs
PublikationsstatusVeröffentlicht - 1 Jan 2019

ASJC Scopus subject areas

  • Mikrobiologie
  • !!Microbiology (medical)

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