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

• Published in: Journal of medicinal chemistry Vol. 64; no. 2; pp. 1116 - 1126
• Main Authors: Li, Zhuang, Tu, Jie, Han, Guiyan, Liu, Na, Sheng, Chunquan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.01.2021; Amer Chemical Soc
• Subjects: Animals; Azoles - therapeutic use; Biofilms - drug effects; Candida albicans - drug effects; Candida albicans - enzymology; Candidiasis - drug therapy; Candidiasis - microbiology; Carbolines - chemical synthesis; Carbolines - therapeutic use; Carbolines - toxicity; Chemistry, Medicinal; Drug Resistance, Fungal - drug effects; Drug Therapy, Combination; Female; Fluconazole - pharmacology; Fungal Proteins - drug effects; Fungi - drug effects; Fungi - enzymology; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylase Inhibitors - toxicity; Humans; Life Sciences & Biomedicine; Liver - pathology; Membrane Transport Proteins - drug effects; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pharmacology & Pharmacy; Science & Technology; CDR; DISCOVERY; THERAPY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01763

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 Candida albicans infection. In particular, compound D12 showed excellent in vitro and in vivo synergistic antifungal efficacy with fluconazole to treat azole-resistant candidiasis. It cooperated with fluconazole in reducing the virulence of C. albicans 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 ERG11 and efflux gene CDR1. Taken together, fungal HDAC inhibitor D12 offered a promising lead compound for combinational treatment of azole-resistant candidiasis.