Butyrolactol A potentiates caspofungin efficacy against resistant fungi via phospholipid flippase inhibition

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  • AFAline A. Fiebig
    Aline A. Fiebig
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Abstract
Summary: Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris , a notorious global threat, is also increasingly resistant. We performed a natural product extract screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris . Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1–Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1•butyrolactol A complex revealed that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.
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Funding Information
  • Canadian Institutes of Health Research (FDN148463)
  • Canadian Institutes of Health Research (PJT190298)
  • Canadian Institutes of Health Research (FDN-154288)
  • Canadian Institutes of Health Research (FRN 143215)
  • Canadian Institutes of Health Research (MOP-119391)
  • Canadian Institutes of Health Research (PJT-156067)
  • National Institutes of Health (R01CA231466)
  • National Institutes of Health (AI39115-27)
  • National Institutes of Health (AI050113-20)
  • National Institutes of Health (AI170543-02)
  • National Institutes of Health (AI172451-02)
  • National Institutes of Health (AI133654-07)
  • National Institutes of Health predoctoral fellowship (F31 AI150120)
  • National Institutes of Health (AI053721-20)
  • National Institutes of Health (R01AI127375)
  • CIFAR program Fungal Kingdom: Threats & Opportunities (CF-0185)
  • CIFAR program Fungal Kingdom: Threats & Opportunities (CF-0116)
  • Canada Research Chairs

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