NT-A9, a new triazole, exhibits potent antifungal activity against Candida and Cryptococcus species through potent ergosterol biosynthesis inhibition
4 affiliations
- 1Department of Pharmacy, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- 2School of Pharmacy, Naval Medical University, Shanghai, China
- 3Department of Laboratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- 4Key Laboratory of Pathogen-Host Interaction, Ministry of Education, School of Medicine, Tongji University, Shanghai, China
Abstract
Invasive fungal infections (IFIs) remain a major global health threat due to limited therapeutic options and rising azole resistance. NT-a9 is a novel triazole antifungal with potent activity against Candida and Cryptococcus species via strong inhibition of ergosterol biosynthesis. In vitro, NT-a9 exhibited potent and sustained antifungal activity against clinical isolates, with superior potency compared to fluconazole (FLC). It also displayed a prolonged post-antifungal effect (PAFE) against most Candida species, a property rarely seen in conventional azoles. Resistance profiling demonstrated that NT-a9 possesses a high genetic barrier, fully suppressing resistant mutant emergence in Cryptococcus species and maintaining stable susceptibility in Candida albicans during 28 days of continuous exposure. NT-a9 retained potent activity against FLC-resistant Cryptococcus neoformans and multidrug-resistant Candida auris, with minimal influence from drug efflux mechanisms. In murine invasive candidiasis, a single low dose of NT-a9 achieved 100% survival and markedly reduced renal fungal burden, significantly outperforming FLC. NT-a9 also substantially improved survival in mice infected with FLC-resistant C. auris. Mechanistically, NT-a9 binds Erg11 with much higher affinity than FLC by forming key hydrogen bonds with Gly307 and His377, leading to irreversible ergosterol depletion, toxic sterol accumulation, and severe fungal membrane damage. Transcriptomic analysis further confirmed that NT-a9 extensively disrupts sterol biosynthesis and triggers compensatory gene expression that reinforces its antifungal action. As a novel triazole integrating long-lasting efficacy, a high resistance barrier, and potent activity against pan-azole-resistant pathogens, NT-a9 represents a promising clinical candidate for treating IFIs.
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BibTeX
@article{zhu2026nta9,
title = {{NT-A9, a new triazole, exhibits potent antifungal activity against Candida and Cryptococcus species through potent ergosterol biosynthesis inhibition}},
author = {Shuo Zhu and Tingjunhong Ni and Lu Gao and Wanqian Li and Dazhi Zhang and Wenjuan Wu and Yuanying Jiang and Hui Lu},
journal = {Antimicrobial Agents and Chemotherapy},
year = {2026},
month = aug,
doi = {10.1128/aac.00768-26},
url = {https://doi.org/10.1128/aac.00768-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NT-A9, a new triazole, exhibits potent antifungal activity against Candida and Cryptococcus species through potent ergosterol biosynthesis inhibition
AU - Shuo Zhu
AU - Tingjunhong Ni
AU - Lu Gao
AU - Wanqian Li
AU - Dazhi Zhang
AU - Wenjuan Wu
AU - Yuanying Jiang
AU - Hui Lu
PY - 2026
DA - 2026/08/05
JO - Antimicrobial Agents and Chemotherapy
DO - 10.1128/aac.00768-26
UR - https://doi.org/10.1128/aac.00768-26
AB - Invasive fungal infections (IFIs) remain a major global health threat due to limited therapeutic options and rising azole resistance. NT-a9 is a novel triazole antifungal with potent activity against Candida and Cryptococcus species via strong inhibition of ergosterol biosynthesis. In vitro, NT-a9 exhibited potent and sustained antifungal activity against clinical isolates, with superior potency compared to fluconazole (FLC). It also displayed a prolonged post-antifungal effect (PAFE) against most Candida species, a property rarely seen in conventional azoles. Resistance profiling demonstrated that NT-a9 possesses a high genetic barrier, fully suppressing resistant mutant emergence in Cryptococcus species and maintaining stable susceptibility in Candida albicans during 28 days of continuous exposure. NT-a9 retained potent activity against FLC-resistant Cryptococcus neoformans and multidrug-resistant Candida auris, with minimal influence from drug efflux mechanisms. In murine invasive candidiasis, a single low dose of NT-a9 achieved 100% survival and markedly reduced renal fungal burden, significantly outperforming FLC. NT-a9 also substantially improved survival in mice infected with FLC-resistant C. auris. Mechanistically, NT-a9 binds Erg11 with much higher affinity than FLC by forming key hydrogen bonds with Gly307 and His377, leading to irreversible ergosterol depletion, toxic sterol accumulation, and severe fungal membrane damage. Transcriptomic analysis further confirmed that NT-a9 extensively disrupts sterol biosynthesis and triggers compensatory gene expression that reinforces its antifungal action. As a novel triazole integrating long-lasting efficacy, a high resistance barrier, and potent activity against pan-azole-resistant pathogens, NT-a9 represents a promising clinical candidate for treating IFIs.
SN - 0066-4804
SN - 1098-6596
ER -