Virtual screening and drug repositioning as strategies for the discovery of new antifungal inhibitors of oxidosqualene cyclase.

Candidiasis is the most common fungal infection in immunocompromised patients, and Candida albicans is the fourth leading agent of nosocomial infections. Mortality from this infection is significant; however, the therapeutic treatment is limited, which demands the search for new drugs and new targets. In this context, oxidosqualene cyclase (OSC) catalyzes the cyclization of the 2,3-oxidosqualene to form lanosterol, an intermediate of ergosterol biosynthesis. Therefore, this enzyme constitutes an attractive therapeutic target. Thus, the aim of this study is to identify potential inhibitors of C. albicans OSC (CaOSC) from a marketed drugs database in order to discover new antifungal agents. The CaOSC 3D model was constructed using the Swiss-Model server and important features for CaOSC inhibition were identified by molecular docking of known inhibitors using Autodock Vina 1.1.2. Subsequently, virtual screening helped to identify calcitriol, the active form of vitamin D, and other four drugs, as potential inhibitors of CaOSC. The selected drugs presented an interesting pattern of interactions with this enzyme, including hydrogen bond with Asp450, a key residue in the active site. Thus, the antifungal activity of calcitriol was evaluated in vitro against Candida spp strains. Calcitriol showed antifungal activity against C. albicans and C. tropicalis, which reinforces the potential of this compound as candidate of CaOSC inhibitor. In short, the present study provides important insights for the development of new oxidosqualene cyclase inhibitors as antifungals.

Schinus terebinthifolius (Brazilian Peppertree) extract used as antifungal to control Candida spp. in planktonic cultures and biofilms / Extrato de Schinus terebinthifolius (pimenta rosa) utilizado como antifúngico para controlar Candida spp. em culturas planctônicas e biofilmes

Objective: The use of medicinal plants may be an alternative method for the control of Candida spp. Responsible for human infections. This study evaluated the antifungal effect of Schinus terebinthifolius extract (Brazilian Peppertree) on C. albicans, C. dubliniensis, C. glabrata, and C. krusei planktonic cultures and bio films. Material and Methods: Minimum inhibitory concentration (MIC) and minimum fungal concentration (MFC) of the plant extract were determined by the broth microdilution method. Biofilms formed in microplate wells were exposed to the extract for 5 min (50, 100 and 200 mg/mL) or 24 h (25, 50 and 100 mg/mL). After determination of colony-forming units per milliliter (CFU/mL), the data were analyzed by one-way ANOVA and Tukey's Test (P ≤ 0.05). Results: Different MIC (mg/mL) were found, such as 0.39 (C. dubliniensis), 1.56 (C. albicans), and 3.13 (C. glabrata and C. krusei). Besides, MFC (mg/mL) of 0.78 (C. dubliniensis) and 3.13 (C. albicans, C. glabrata and C. krusei) were also observed. Regarding the biofilms, significant reductions (log10) were found after 5 min and 24 h exposure to the plant extract, compared to the control group. However, C. dubliniensis was significantly affected only in 24 h treatment. Conclusion: S. terebinthifolius extract presented a significant antifungal effect on C. albicans, C. dubliniensis, C. glabrata, and C. Krusei both in planktonic cultures and biofilms (AU)

Objetivo: O uso de plantas medicinais pode ser um método alternativo para o controle de Candida spp. responsáveis por infecções humanas. Este estudo avaliou o efeito antifúngico do extrato de Schinus terebinthifolius (pimenta rosa) sobre culturas planctônicas e biofilmes de C. albicans, C. dubliniensis, C. glabrata e C. krusei. Material e Métodos: Concentração inibitória mínima (CIM) e concentração fungicida mínima (CFM) do extrato vegetal foram determinadas pelo método de micro diluição em caldo. Biofilmes formados em poços de microplacas foram expostos ao extrato por 5 min (50, 100 e 200 mg/mL) ou 24 h (25, 50 e 100 mg/mL). Após determinação de unidades formadoras de colônias por mililitro (UFC/mL), os dados foram analisados por one-way ANOVA e Teste de Tukey (P ≤ 0,05). Resultados: Foram encontradas diferentes CIM (mg/mL), como 0,39 (C. dubliniensis),1,56 (C. albicans) e 3,13 (C. glabrata e C. krusei). Além disso, CFM (mg/mL) de 0,78 (C. dubliniensis) e 3,13 (C. albicans, C. glabrata e C. krusei) também foram observadas. Em relação aos biofilmes, foram encontradas reduções significativas (log10) após 5 min e 24 h de exposição ao extrato vegetal, em comparação ao grupo controle. No entanto, C. dubliniensis foi significativamente afetada apenas no tratamento de 24 h. Conclusão: O extrato de S. terebinthifolius apresentou efeito antifúngico significativo sobre C. albicans, C. dubliniensis, C. glabrata e C. Krusei, tanto em culturas planctônicas quanto em biofilmes. (AU)