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

doi:10.2217/fmb-2019-0052

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^*

^*Corresponding author for this work

Institute of Biochemistry (6480)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	969-980
Number of pages	12
Journal	Future Microbiology
Volume	14
Issue number	11
DOIs	https://doi.org/10.2217/fmb-2019-0052
Publication status	Published - 1 Jan 2019

Keywords

antifungal
chorismate synthase
inhibitor
paracoccidioidomycosis
systemic mycosis

ASJC Scopus subject areas

Microbiology
Microbiology (medical)

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title = "New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis",

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.",

keywords = "antifungal, chorismate synthase, inhibitor, paracoccidioidomycosis, systemic mycosis",

author = "Bueno, {Paulo S.A.} and Rodrigues-Vendramini, {Franciele A.V.} and Marina Toplak and Peter Macheroux and Kioshima, {{\'E}rika S.} and Seixas, {Flavio A.V.}",

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doi = "10.2217/fmb-2019-0052",

language = "English",

volume = "14",

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journal = "Future Microbiology",

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T1 - New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis

AU - Bueno, Paulo S.A.

AU - Rodrigues-Vendramini, Franciele A.V.

AU - Toplak, Marina

AU - Macheroux, Peter

AU - Kioshima, Érika S.

AU - Seixas, Flavio A.V.

PY - 2019/1/1

Y1 - 2019/1/1

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.

AB - 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.

KW - antifungal

KW - chorismate synthase

KW - inhibitor

KW - paracoccidioidomycosis

KW - systemic mycosis

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DO - 10.2217/fmb-2019-0052

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AN - SCOPUS:85071158327

SN - 1746-0913

VL - 14

SP - 969

EP - 980

JO - Future Microbiology

JF - Future Microbiology

IS - 11

ER -

New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis

Abstract

Keywords

ASJC Scopus subject areas

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