Antifungal mechanism of [Ru III (NH 3 ) 4 catechol] + complex on fluconazole-resistant Candida tropicalis

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Candidiasis, a major opportunistic mycosis caused by <span style="font-style:italic;">Candida</span> sp., may comprise life-threatening systemic infections. The incidence of non-<span style="font-style:italic;">albicans</span> species is rising, particularly in South America and they are frequently drug resistant, causing unresponsive cases. Thus, novel antimycotic agents are required. Here we tested the antifungal activity of [Ru^III(NH₃)₄catechol]⁺ complex (RuCat), approaching possible action mechanisms on fluconazole-resistant <span style="font-style:italic;">Candida tropicalis</span>. RuCat significantly (<span style="font-style:italic;">P</span> < 0.05) inhibited the growth and viability of <span style="font-style:italic;">C. tropicalis</span> dose-dependently (IC₅₀ 20.3 μM). Cytotoxicity of RuCat upon murine splenocytes was lower (Selectivity Index = 16). Scanning electron microscopy analysis showed pseudohyphae formation, yeast aggregation and surface damage. RuCat-treated samples investigated by transmission electron microscopy showed melanin granule trafficking to cell surfaces and extracellular milieu. Surface-adherent membrane fragments and extracellular debris were also observed. RuCat treatment produced intense H₂DCFDA labeling, indicating reactive oxygen species (ROS) production which caused increased lipoperoxidation. ROS are involved in the fungicidal effect as <span style="font-style:italic;">N</span>-acetyl-L-cysteine completely restored cell viability. Calcofluor White chitin staining suggests that 70 or 140 μM RuCat treatment for 2 h affected cell-wall structure. PI labeling indicated necrotic cell death. The present data indicate that RuCat triggers ROS production, lipoperoxidation and cell surface damage, culminating in selective necrotic death of drug-resistant <span style="font-style:italic;">C. tropicalis.</span></span>

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