New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans <i>In Vitro</i> and <i>In Vivo</i>

Abstract

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 a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities <i>in vitro</i> and <i>in vivo</i> NT-a9 showed a wide range of activities against several pathogenic fungi <i>in vitro</i>, including <i>Cryptococcus neoformans</i>, <i>Cryptococcus gattii</i>, <i>Candida albicans</i>, <i>Candida krusei</i>, <i>Candida tropicalis</i>, <i>Candida glabrata</i>, and <i>Candida parapsilosis</i>, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against <i>C. neoformans</i>, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in <i>C. neoformans</i>, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The <i>in vivo</i> efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 10⁶ CFU of <i>C. neoformans</i> strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.