Molecular landscape of the fungal plasma membrane and implications for antifungal action

TL;DR

This study explores the organization of proteins in the fungal plasma membrane and how antifungal drugs affect them.

Contribution

The study reveals how antifungal drugs disrupt membrane protein complexes and the role of lipids in drug interactions.

Findings

Caspofungin treatment disrupts membrane protein complex distribution and alters membrane properties.

Sphingolipid biosynthesis perturbation modulates drug susceptibility and affects membrane protein organization.

Abstract

Fungal plasma membrane proteins represent key therapeutic targets for antifungal agents, yet their native structure and spatial distribution remain poorly characterized. Herein, we employ an integrative approach to investigate the organization of plasma membrane protein complexes in Candida glabrata, focusing on two abundant and essential membrane proteins, the β-(1,3)-glucan synthase (GS) and the proton pump Pma1. We show that treatment with caspofungin, an echinocandin antifungal that targets GS, disrupts the native distribution of membrane protein complexes and alters membrane biophysical properties. Perturbation of the sphingolipid biosynthesis further modulates drug susceptibility, revealing that the lipid environment plays an integral role in membrane protein organization and GS-echinocandin interactions. Our work highlights the importance of characterizing membrane proteins in their native context to understand their functions and inform the development of novel antifungal therapies.

Proteins in the fungal plasma membrane are key antifungal targets but their native structure and spatial distribution are poorly understood. Here, Jiang et al. use proteomics and cryo-electron tomography to investigate the organisation of membrane proteins in the fungal plasma membrane and how this is affected by antifungal drugs.

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