Novel Carboline Fungal Histone Deacetylase (HDAC) Inhibitors for Combinational Treatment of Azole-Resistant Candidiasis.

Due to the evolution and development of antifungal drug resistance, limited efficacy of existing drugs has led to high mortality in patients with serious fungal infections. To develop novel antifungal therapeutic strategies, herein a series of carboline fungal histone deacetylase (HDAC) inhibitors were designed and synthesized, which had potent synergistic effects with fluconazole against resistant infection. In particular, compound showed excellent and synergistic antifungal efficacy with fluconazole to treat azole-resistant candidiasis. It cooperated with fluconazole in reducing the virulence of by blocking morphological mutual transformation and inhibiting biofilm formation. Mechanism studies revealed that the reversion of drug resistance was due to downregulation of the expression of the azole target gene and efflux gene . Taken together, fungal HDAC inhibitor offered a promising lead compound for combinational treatment of azole-resistant candidiasis.