New Triazole NT-a9 has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo.
Antimicrob Agents Chemother. 2019 Dec 02;:
Authors: Lu RY, Ni TJ, Wu J, Yan L, Lv QZ, Li LP, Zhang DZ, Jiang YY
In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described the leading compound NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo NT-a9 showed wide range activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata and Candida parapsilosis, with MIC values ranging from 0.002 to 1 μg/ml. Particularly, NT-a9 exhibited excellent efficacy against C. neoformans with MIC value as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in sterols content in C. neoformans, similar to fluconazole. In addition, NT-a9 possessed a relatively low cytotoxicity and high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated cryptococcosis model. Mice were infected intravenously with 1.8 ¡Á 106 CFU C. neoformans H99. In the survival study, NT-a9 significantly prolonged mice survival time compared with the control group, the isavuconazole, fluconazole or amphotericin B treated groups. Especially, 4 and 8 mg/kg of NT-a9 rescued all the mice with a survival of 100%. In the fungal burden study, NT-a9 also significantly reduced fungal burden in brains and lungs, while fluconazole and amphotericin B only reduced fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.
PMID: 31791946 [PubMed - as supplied by publisher]