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TitleButyrolactol A is a phospholipid flippase inhibitor that potentiates the bioactivity of caspofungin against resistant fungi.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateJan 6, 2025
AuthorsXuefei Chen / H Diessel Duan / Michael J Hoy / Kalinka Koteva / Michaela Spitzer / Allison K Guitor / Emily Puumala / Guanggan Hu / Bonnie Yiu / Sommer Chou / Zhuyun Bian / Amelia Bing Ya Guo / Sheng Sun / Nicole Robbins / Michael A Cook / Ray Truant / Lesley T MacNeil / Eric D Brown / James W Kronstad / 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 antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the ...Fungal infections cause millions of deaths annually and are challenging to treat due to limited antifungal options and increasing drug resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while , a notorious global threat, is also increasingly resistant. We performed a natural product extract screen for rescue of the activity of the echinocandin caspofungin against H99, identifying butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including . Mode of action studies revealed that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryoelectron-microscopy analysis of the Apt1●butyrolactol A complex revealed that the flippase is locked in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.
External linksbioRxiv / PubMed:39829750 / PubMed Central
MethodsEM (single particle)
Resolution2.72 - 3.27 Å
Structure data

EMDB-47334: Cryo-EM consensus map of the C. neoformans lipid flippase Apt1-Cdc50 bound with butyrolactol A in the E2P state
Method: EM (single particle) / Resolution: 2.72 Å

EMDB-47335: Cryo-EM focused map masking butyrolactol A binding site of the C. neoformans lipid flippase Apt1-Cdc50 bound with butyrolactol A in the E2P state
Method: EM (single particle) / Resolution: 2.93 Å

47338

9dzu

EMDB-47338, PDB-9dzu:
Cryo-EM structure of the C. neoformans lipid flippase Apt1-Cdc50 bound with butyrolactol A in the E2P state
Method: EM (single particle) / Resolution: 2.72 Å

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

Chemicals

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

ChemComp-BEF:
BERYLLIUM TRIFLUORIDE ION

ChemComp-MG:
Unknown entry

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

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

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