Islay Lima Magalhães¹, Bruno Coêlho Cavalcanti¹, Marina Duarte Pinto Lobo², João Batista de Andrade Neto^1,3,4, Hélio Vitoriano Nobre Júnior^1,3, Manoel Odorico de Moraes¹

Introduction: Candida spp. is the third most isolated agent in fungal infections acquired in hospitals. In Latin America, as well as in Brazil, the candidemia rate remains high, where several researchers have described the importance of Candida tropicalis as one of the most commonly isolated yeast species. Fluconazole (FLC) is the main agent used for the primary treatment of invasive fungal infections and its indiscriminate use is cited as a major cause for the resistance emergence in Candida non-albicans species. Our group recently demonstrated that naphthofuranquinones (NFQs) exhibited significant antifungal activity against fluconazole-resistant Candida spp. strains, mediated through the generation of free radicals and the deleterious effects thereof. Materials and methods: NFQs used here were: 2-(iodomethyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (1), 2-[iodomethyl]-2,3 dihydronaphtho[1,2-b]furan-4,5-dione (2) and 2-methyl2,3-dihydronaphtho[1,2-b]furan-4,5-dione (3). FLC-resistant C. tropicalis (laboratory collection - LABIMAN/UFC) were cultivated in YPD medium [1% (m/v) yeast extract, 2% (m/v) peptone, 2% (m/v) dextrose] at 37 °C, and cell suspensions were prepared from cultures on exponential growth phase. Later, NFQs, at their minimal inhibitory concentration, were added to final concentrations of 51 μg/mL (1 and 2) and 32 μg/mL (3) during 24 h at 35 °C. Protein identification and quantification were performed by Mass Spectrometry (MS) and then using Protein Lynx Software Global Server v.2.4 against a C. tropicalis annotated database, accessible on UNIPROT.  Only proteins with a differential expression and absolute ratio values of > 1.5 (up-regulated) and < 0.66 (down-regulated) were considered. Remaining proteins, with ratio values between 1.5 and 0.66, were considered to be unchanged at expression levels. Discussion: Until now, a total of 16 proteins were identified  for 1, of which only four had increased expression levels (ubiquitin C , peroxiredoxin TSA1, heat shock protein 70 and histone H2B.1).  For 2 and 3, a total of 17 proteins were identified, five of which were highly expressed (ubiquitin C, peroxiredoxin TSA1, histone H2B.1, alcohol dehydrogenase and phosphoglyceratemutase 1). Conclusion: It was observed that compounds 2 and 3 appear to induce changes in the aerobic respiration, as a result of protein alcohol dehydrogenase fragment\'s increased expression, where these changes seem to potentiate the antifungal effect of these two molecules. The changes in aerobic respiration can lead to a reduction in intracellular ATP and an increase in free radical levels contributing to the antifungal potential of these molecules.

Agradecimentos: CNPq, CAPES and FUNCAP.