Promising antifungal properties of the orally active autophagy inhibitor SBP-7455 against fluconazole-resistant <i>Candida</i> clinical isolates

Abstract

Candida species, the single most common cause of fungal infections, are major opportunistic pathogens. Novel antifungal agents are needed to address the threat of Candida infections resistant to first-line antifungal agents and those that are multi-drug resistant, both being increasingly reported. Here, we explore the antifungal properties of the novel autophagy inhibitor SBP-7455, whose anticancer effects have been recently described. Using broth microdilution, SBP-7455 inhibited the fluconazole-resistant standard C. albicans strain with minimum inhibitory concentration (MIC) values of 43.91 and 21.95 µM in the presence and absence of d-glucose, respectively. SBP-7455 inhibited the growth of six fluconazole-resistant Candida clinical isolates (MIC range 5.48-87.82 µM). Using the checkerboard assay, the fluconazole-resistant standard strain (MIC > 250 µg/ml) was rendered sensitive (MIC = 3.9 µg/ml) to fluconazole when combined with SBP-7455, but combining SBP-7455 with chloroquine was antagonistic. Compared with control, SBP-7455 treated cell membranes showed disrupted integrity and bulging on SEM images. Treatment with SBP-7455 significantly (P < 0.01) increased reduced glutathione levels with no significant change in nitric oxide levels, possibly adapting to oxidative stress induced by autophagy inhibition. Taken together, our results report for the first time the promising antifungal effects of the dual autophagy inhibitor SBP-7455 against fluconazole-resistant Candida, worthy of further investigation.