Invasive fungal infections, particularly cryptococcal meningitis (CM) caused by Cryptococcus neoformans , represent a severe and increasingly significant global health threat. CM accounts for approximately 15%–20% of HIV/AIDS-related deaths worldwide. The World Health Organization has listed Cryptococcus neoformans as a highest-priority pathogen in its critical fungal pathogen list. However, current antifungal therapies face major challenges, including frequent drug resistance, significant toxicity, and limited mechanisms of action. Therefore, there is an urgent need to develop novel anti-cryptococcal agents with new scaffolds and mechanisms.
Research teams led by Professors Na Liu and Chunquan Sheng from Naval Medical University (Second Military Medical University), in collaboration with Professor Wei Xu from Fujian University of Traditional Chinese Medicine, conducted phenotypic screening of a commercial compound library and identified the spiroquinoxaline compound S9 as a selective anti-cryptococcal lead. Through systematic structural optimization, three series of novel spiroquinoxaline derivatives were designed and synthesized.
Among them, compound B1 exhibited potent inhibitory activity in vitro against seven different subtypes of Cryptococcus neoformans (MIC₈₀ = 1–4 μg/mL), outperforming fluconazole. In a CM mouse model, B1 significantly reduced fungal burden in the brain. Mechanistic studies integrating transcriptomics, proteomics, and biochemical assays demonstrated that B1 markedly suppressed the expression of key genes such as LAC2 , CAP10 , CAP59 , and CAP60 , thereby inhibiting critical virulence factors, including capsule formation, biofilm development, urease activity, and melanin production. Additionally, B1 induced the accumulation of intracellular reactive oxygen species and lipid peroxides, suggesting that it exerts its antifungal effects through oxidative stress-mediated cellular damage.
This study not only presents a novel promising lead compound with favorable in vivo safety but also reveals a potential therapeutic strategy targeting fungal virulence and oxidative stress defense pathways. The researchers stated, "This work provides a new arsenal for the development of antifungal drugs against cryptococcosis".
See the article:
Discovery of novel spiroquinoxaline derivatives as potent antifungal agents for the treatment of cryptococcal meningitis ( https://doi.org/10.1080/21501203.2026.2682936 )
Discovery of novel spiroquinoxaline derivatives as potent antifungal agents for the treatment of cryptococcal meningitis
24-Jun-2026