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

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 in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a 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 × 106 CFU of C. neoformans 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.

A New Antifungal Agent (4-phenyl-1, 3-thiazol-2-yl) Hydrazine Induces Oxidative Damage in Candida albicans

“…Cytotoxicity of 31C was assessed by cell counting kit-8 (CCK-8) as described (Lu et al, 2020 ). HUVECs were cultured in DMEM mediums containing 10% fetal bovine serum (FBS) and used to evaluate the toxicity of 31C.…”

Synthesis of Hemiprotonic Phenanthroline–Phenanthroline+ Compounds with both Antitumor and Antimicrobial Activity

“…C. neoformansis is a zoonotic fungal pathogen that can infect regular hosts and immunocompromised individuals, especially patients with HIV, malignant tumors, and therapeutic immunosuppression C.…”

“…were placed at room temperature for 1 year or above, even heated to more than 100 °C, they could still maintain their respective structures. In the study, ultraviolet (UV) absorption spectra of ph−ph + and its derivatives in aqueous solution were measured under different temperatures (25,37,60, and 100 °C) to determine their stability. The results are shown in Figure S4.…”

“…24 C. neoformansis is a zoonotic fungal pathogen that can infect regular hosts and immunocompromised individuals, especially patients with HIV, malignant tumors, and therapeutic immunosuppression. 25 C. neoformans can cause fatal encephalitis and pneumonia when animals are infected by the fungus. 26,27 Until now, cryptococcal meningitis has been the most common intracranial infectious fungal disease with a high morbidity and mortality rate in sub-Saharan Africa.…”

Design, Synthesis and Antifungal Evaluation of Novel Pyrylium Salt In Vitro and In Vivo

“…Then, a 100 μL suspension of HUVECs (1 × 10 5 cells/mL) was added to 96-well tissue culture plates and incubated at 37 °C for 3 h. After incubation, the supernatant was replaced by 100 μL of fresh DMEM complete mediums containing different concentrations of XY12 and XY2 . After incubation for 24 h, the supernatant was added with 10 μL of CCK-8 agents and cultured at 37 °C for 2 h. Finally, cell viability was assessed by measuring OD 450 [ 18 ].…”