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<p>Fungal infections pose a serious threat to global human health fueled by the increase in immunosuppressive therapies, medical implants, and transplantation. The emergence of multidrug resistance with limited options of current antifungal drugs are a further constraint. There is thus a clear and unmet need to identify therapeutic targets and develop alternative classes of antifungal agents. Here, we hypothesize that dual targeting of key regulatory genes of fungal cell wall synthesis (<i>FKS1</i> encoding β−1,3-glucan synthase and <i>CHS3</i> encoding chitin synthase) can synergistically inhibit fungal growth. Based on iterative designs, we generate a small library of fungal-targeted nanoconstructs, and identify a lead construct (FTNx) that shows preferential accumulation in fungal cells over mammalian cells and leads to prominent antifungal effects in vitro. We further show that FTNx is highly effective in a mouse model of disseminated candidiasis, demonstrating diminished fungal growth and enhanced survival rate. This strategy appears promising as an effective treatment for fungal infections in mammalian hosts.</p>

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Effective treatment of systemic candidiasis by synergistic targeting of cell wall synthesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

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  • Ju Yeon Chung,
  • Yoon-Kyoung Hong,
  • Eunhee Jeon,
  • Seungju Yang,
  • Ayoung Park,
  • Ralph Weissleder,
  • Yong Pil Chong,
  • Hyun Jung Chung

摘要

Fungal infections pose a serious threat to global human health fueled by the increase in immunosuppressive therapies, medical implants, and transplantation. The emergence of multidrug resistance with limited options of current antifungal drugs are a further constraint. There is thus a clear and unmet need to identify therapeutic targets and develop alternative classes of antifungal agents. Here, we hypothesize that dual targeting of key regulatory genes of fungal cell wall synthesis (FKS1 encoding β−1,3-glucan synthase and CHS3 encoding chitin synthase) can synergistically inhibit fungal growth. Based on iterative designs, we generate a small library of fungal-targeted nanoconstructs, and identify a lead construct (FTNx) that shows preferential accumulation in fungal cells over mammalian cells and leads to prominent antifungal effects in vitro. We further show that FTNx is highly effective in a mouse model of disseminated candidiasis, demonstrating diminished fungal growth and enhanced survival rate. This strategy appears promising as an effective treatment for fungal infections in mammalian hosts.