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

de Xuefei 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 e Gerard D. Wright

Publicado: 6 de janeiro de 2025
Servidor: bioRxiv
DOI: 10.1101/2025.01.06.630955

Resumo

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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Avaliação PREreview de Gabriel C. Lander et al.

De autoria de Gabriel C. Lander e Jan-Hannes Schäfer

This study from Chen et al. addresses the rise of antifungal resistance, which is of increasing biomedical concern due to our limited number of antifungal drugs. The authors leveraged a natural product screen on microbial extracts of resistant fungal pathogens to identify butyrolactol A as a…

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

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