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TitleButyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi.
Journal, issue, pagesCell, Vol. 189, Issue 2, Page 620-639.e28, Year 2026
Publish dateJan 22, 2026
AuthorsXuefei Chen / H Diessel Duan / Michael J Hoy / Kalinka Koteva / Michaela Spitzer / Allison K Guitor / Emily Puumala / Aline A Fiebig / Guanggan Hu / Bonnie Yiu / Sommer Chou / Zhuyun Bian / Yeseul Choi / Amelia Bing Ya Guo / Wenliang Wang / Sheng Sun / Nicole Robbins / Anna Floyd Averette / Michael A Cook / Ray Truant / Lesley T MacNeil / Eric D Brown / James W Kronstad / Brian K Coombes / Leah E Cowen / Joseph Heitman / Huilin Li / Gerard D Wright /
PubMed AbstractFungal 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 ...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 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 reveal that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals 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.
External linksCell / PubMed:41478284 / PubMed Central
MethodsEM (single particle)
Resolution2.95 - 3.27 Å
Structure data

47339

9dzv

EMDB-47339, PDB-9dzv:
Cryo-EM structure of the C. neoformans lipid flippase Apt1-Cdc50 in the E1 state
Method: EM (single particle) / Resolution: 3.27 Å

70618

9omv

EMDB-70618, PDB-9omv:
Cryo-EM structure of the C. neoformans lipid flippase Apt1-Cdc50 bound with butyrolactol A in the E2P state
Method: EM (single particle) / Resolution: 2.95 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MG:
Unknown entry

ChemComp-BEF:
BERYLLIUM TRIFLUORIDE ION

PDB-1bd6:
7-FE FERREDOXIN FROM BACILLUS SCHLEGELII, NMR, MINIMIZED AVERAGE STRUCTURE

Source
  • cryptococcus neoformans var. grubii h99 (fungus)
KeywordsLIPID TRANSPORT / Cryptococcus neoformans / lipid flippase / P4-ATPase / Cdc50 protein / butyrolactol A / TRANSLOCASE/INHIBITOR / TRANSLOCASE-INHIBITOR complex

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