title: 1,10-Phenanthroline-5,6-Dione-Based Compounds Are Effective in Disturbing Crucial Physiological Events ofPhialophora verrucosa.
abstract: Phialophora verrucosais a dematiaceous fungus able to cause chromoblastomycosis, phaeohyphomycosis and mycetoma. All these fungal diseases are extremely difficult to treat and often refractory to the current therapeutic approaches. Therefore, there is an urgent necessity to develop new antifungal agents to combat these mycoses. In this context, the aim of the present work was to investigate the effect of 1,10-phenanthroline-5,6-dione (phendione) and its metal-based derivatives [Ag(phendione)2]ClO4= ([Ag(phendione)2]+) and [Cu(phendione)3](ClO4)2.4H2O = ([Cu(phendione)3]2+) on crucial physiological events ofP. verrucosaconidial cells. Using the CLSI protocol, we have shown that phendione, [Ag(phendione)2]+and [Cu(phendione)3]2+were able to inhibit fungal proliferation, presenting MIC/IC50values of 12.0/7.0, 4.0/2.4, and 5.0/1.8 μM, respectively. [Cu(phendione)3]2+had fungicidal action and when combined with amphotericin B, both at sub-MIC (½ × MIC) concentrations, significantly reduced (~40%) the fungal growth. Cell morphology changes inflicted by phendione and its metal-based derivatives was corroborated by scanning electron microscopy, which revealed irreversible ultrastructural changes like surface invaginations, cell disruption and shrinkages. Furthermore, [Cu(phendione)3]2+and [Ag(phendione)2]+were able to inhibit metallopeptidase activity secreted byP. verrucosaconidia by approximately 85 and 40%, respectively. Ergosterol content was reduced (~50%) after the treatment ofP. verrucosaconidial cells with both phendione and [Ag(phendione)2]+. To different degrees, all of the test compounds were able to disturb theP. verrucosaconidia-into-mycelia transformation. Phendione and its Ag+and Cu2+complexes may represent a promising new group of antimicrobial agents effective at inhibitingP. verrucosagrowth and morphogenesis.
authors.affiliation: Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz Rio de Janeiro, Brazil.
authors.forename: Marcela Queiroz
authors.initials: MQ
authors.lastname: Granato
authors.affiliation: Laboratório de Investigação de Peptidases, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil; Programa de Pós-Graduação em Bioquímica, Instituto de Química, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil.
authors.forename: Diego de Souza
authors.initials: DS
authors.lastname: Gonçalves
authors.affiliation: Laboratório de Tecnologia em Cultura de Células, Centro Universitário Estadual da Zona Oeste (UEZO) Duque de Caxias, Brazil.
authors.forename: Sergio Henrique
authors.initials: SH
authors.lastname: Seabra
authors.affiliation: Chemistry Department, Maynooth University, National University of Ireland Maynooth, Ireland.
authors.forename: Malachy
authors.initials: M
authors.lastname: McCann
authors.affiliation: Centre for Biomimetic and Therapeutic Research, Focas Research Institute, Dublin Institute of Technology Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Devereux
authors.affiliation: Laboratório de Investigação de Peptidases, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil; Programa de Pós-Graduação em Bioquímica, Instituto de Química, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil.
authors.forename: André Luis Souza
authors.initials: AL
authors.lastname: Dos Santos
authors.affiliation: Laboratório de Taxonomia, Bioquímica e Bioprospecção de Fungos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz Rio de Janeiro, Brazil.
authors.forename: Lucimar Ferreira
authors.initials: LF
authors.lastname: Kneipp
keywords: 1,10-phenanthroline-5,6-dione; Phialophora verrucosa; antifungal activity; chromoblastomycosis; metal-based drugs