International journal of antimicrobial agents · 2026
Antifungal and immunomodulatory activities of dihydroartemisinin-loaded chitosan nanoparticles against fluconazole‑resistant Candida tropicalis.
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Yang Min, Liu Yan, Xu Kunyu, Wang Peike, Wang Ayi, Zhu Binxia, Su Lin, Zeng Yali, Zhang Qingbi
Аннотация
OBJECTIVES: Invasive fungal infections, such as those caused by fluconazole-resistant Candida tropicalis, pose an important threat to immunocompromised patients, with mortality rates ranging from 55 to 60%. The rise of clinically resistant C. tropicalis has compounded the difficulties in treatment, highlighting the urgent need for the development of novel antifungal agents. This study builds on previous research to evaluate the antifungal efficacy of dihydroartemisinin-loaded chitosan nanoparticles (DHA-CS NPs) against fluconazole-resistant C. tropicalis and elucidates their mechanisms of action.
METHODS: In vitro, antifungal activity was assessed via MIC/MFC determination, time‑kill kinetics, Scanning electron microscopy observation, and multi‑omics analyses, with filipin staining and RT‑qPCR used to verify ergosterol pathway genes (ERG3, HAP1, and UPC2). In vivo, efficacy was evaluated in a murine model by measuring fungal burden, immune markers (IL‑6, TNF‑α, and TLR2), and tissue damage.
RESULTS: DHA-CS NPs demonstrated potent antifungal activity, with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of 7.5 and 15 µg/mL, respectively, achieving 95.75% inhibition at the MIC. The antifungal effect was concentration-dependent, with sterilization achieved in 4 h at 4 × MIC. Scanning electron microscopy revealed that DHA-CS NPs compromised the integrity of the fungal cell membrane. Metabolomic and transcriptomic analyses revealed that DHA-CS NPs significantly disrupted ergosterol biosynthesis, a key component for maintaining fungal cell membrane integrity. Filipin fluorescent staining and RT-qPCR further confirmed this mechanism, showing that DHA-CS NPs inhibited ergosterol synthesis by downregulating critical biosynthetic genes, including ERG3, HAP1, and UPC2 (P < 0.05). In a murine infection model, DHA-CS NPs reduced fungal burden, modulated immune responses (increasing IL-6, TNF-α, and TLR2), and alleviated tissue damage. These findings underscore the potential of DHA-CS NPs as an effective therapeutic approach for drug-resistant candidiasis.
CONCLUSIONS: In summary, DHA-CS NPs present a promising strategy against fluconazole-resistant C. tropicalis, providing a solid scientific foundation for the development of novel anti-resistance therapies.
METHODS: In vitro, antifungal activity was assessed via MIC/MFC determination, time‑kill kinetics, Scanning electron microscopy observation, and multi‑omics analyses, with filipin staining and RT‑qPCR used to verify ergosterol pathway genes (ERG3, HAP1, and UPC2). In vivo, efficacy was evaluated in a murine model by measuring fungal burden, immune markers (IL‑6, TNF‑α, and TLR2), and tissue damage.
RESULTS: DHA-CS NPs demonstrated potent antifungal activity, with minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of 7.5 and 15 µg/mL, respectively, achieving 95.75% inhibition at the MIC. The antifungal effect was concentration-dependent, with sterilization achieved in 4 h at 4 × MIC. Scanning electron microscopy revealed that DHA-CS NPs compromised the integrity of the fungal cell membrane. Metabolomic and transcriptomic analyses revealed that DHA-CS NPs significantly disrupted ergosterol biosynthesis, a key component for maintaining fungal cell membrane integrity. Filipin fluorescent staining and RT-qPCR further confirmed this mechanism, showing that DHA-CS NPs inhibited ergosterol synthesis by downregulating critical biosynthetic genes, including ERG3, HAP1, and UPC2 (P < 0.05). In a murine infection model, DHA-CS NPs reduced fungal burden, modulated immune responses (increasing IL-6, TNF-α, and TLR2), and alleviated tissue damage. These findings underscore the potential of DHA-CS NPs as an effective therapeutic approach for drug-resistant candidiasis.
CONCLUSIONS: In summary, DHA-CS NPs present a promising strategy against fluconazole-resistant C. tropicalis, providing a solid scientific foundation for the development of novel anti-resistance therapies.