Abstract
Candida infections have become a serious public health problem with high mortality rates, especially in immunocompromised patients, since Candida albicans is the major opportunistic pathogen responsible for systemic or invasive candidiasis. Commercially available antifungal agents are restricted and fungal resistance to such drugs has increased; therefore, the development of a more specific antifungal agent is necessary. Using assays for antifungal activity, here we report that two new compounds of 1,3,4-oxadiazoles class (LMM5 and LMM11), which were discovered by in silico methodologies as possible thioredoxin reductase inhibitors, were effective against C. albicans. Both compounds had in vitro antifungal activity with MIC 32 μg/ml. Cytotoxicity in vitro demonstrated that LMM5 and LMM11 were non-toxic in the cell lines evaluated. The kinetic of the time-kill curve suggested a fungistatic profile and showed an inhibitory effect of LMM5 and LMM11 in 12 h that remained for 24 and 36 h, which is better than fluconazole. In the murine systemic candidiasis model by C. albicans, the two compounds significantly reduced the renal and spleen fungal burden. According to the SEM and TEM images, we hypothesize that the mechanism of action of LMM5 and LMM11 is directly related to the inhibition of the enzyme thioredoxin reductase and internally affect the fungal cell. In view of all in vitro and in vivo results, LMM5 and LMM11 are effective therapeutic candidates for the development of new antifungal drugs addressing the treatment of human infections caused by C. albicans.
Highlights
Candida albicans is present in the healthy population as commensal microbiota, this species is classified as an opportunistic fungus
Proportional yeast growth decreased according to the increase of compounds concentrations, we suggest that the antifungal action of LMM5 and LMM11 is not related to mechanisms that cause structural morphological changes
Corroborating this observation, Transmission Electron Microscopy (TEM) photomicrographs (Figure 5) of the longitudinal and transverse sections of the untreated C. albicans control cells showed a homogeneous cytoplasm with a nucleus and mitochondria, surrounded by a defined cell membrane and regular cell wall
Summary
Candida albicans is present in the healthy population as commensal microbiota, this species is classified as an opportunistic fungus. The treatment of invasive fungal infections is restricted to three classes of major antifungal agents: azoles, polyenes and echinocandins. These drugs present disadvantages such as toxicity, the emergence of resistance, complex drug interactions, and significant limitations in activity (Pfaller, 2012; Vandeputte et al, 2012; Sanguinetti et al, 2015; da Matta et al, 2017). Due to this worrying scenario, the development of more specific antifungal agents is necessary. Using assays for antifungal activity, we report that these two new 1,3,4-oxadiazoles class compounds, discovered by in silico methodologies, are possible thioredoxin reductase inhibitors and are effective against C. albicans
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