Abstract
Phialophora verrucosa is 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 of P. verrucosa conidial 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/IC50 values 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 by P. verrucosa conidia by approximately 85 and 40%, respectively. Ergosterol content was reduced (~50%) after the treatment of P. verrucosa conidial cells with both phendione and [Ag(phendione)2]+. To different degrees, all of the test compounds were able to disturb the P. verrucosa conidia-into-mycelia transformation. Phendione and its Ag+ and Cu2+ complexes may represent a promising new group of antimicrobial agents effective at inhibiting P. verrucosa growth and morphogenesis.
Highlights
Phialophora verrucosa is a melanized pathogenic fungus associated with a wide range of neglected diseases including phaeohyphomycosis, mycetoma, keratitis, endophthalmitis, osteomyelitis and endocarditis (Turiansky et al, 1995; Revankar and Sutton, 2010; Sun et al, 2010; Tong et al, 2013)
Human serum albumin (HSA), 1,10-phenanthroline, resazurin, AgClO4, Cu(ClO4)2·6H2O, dimethyl sulfoxide (DMSO), 3-(N-morpholino) propanesulfonic acid (MOPS), itraconazole (ITC), amphotericin B (AMB) ketoconazole (KTC), ergosterol, lanosterol, silica gel 60 plates, Czapek-Dox and Sabouraud-dextrose agar (SDA) components were obtained from Sigma-Aldrich Chemical Co (St Louis, MO, USA)
Aqueous DMSO, which was used as the solvent for all of the test compounds, was inactive against P. verrucosa conidial proliferation
Summary
Phialophora verrucosa is a melanized pathogenic fungus associated with a wide range of neglected diseases including phaeohyphomycosis, mycetoma, keratitis, endophthalmitis, osteomyelitis and endocarditis (Turiansky et al, 1995; Revankar and Sutton, 2010; Sun et al, 2010; Tong et al, 2013) This fungus is especially known to cause chromoblastomycosis (CBM), which is a chronic, progressive disease affecting the cutaneous and subcutaneous tissues (Torres-Guerrero et al, 2012; Krzysciak et al, 2014). Chronic CBM lesions may undergo neoplastic transformation leading to skin cancer (Queiroz-Telles and Santos, 2012) This disease is most prevalent among individuals with outdoor occupations, such as farmers, gardeners and agricultural laborers. New antifungal agents should be studied in order to find out alternative therapeutic ways to treat CBM and other infections caused by P. verrucosa
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