Biophysics meets fungal biology: Characterising the fungal cell envelope and its interactions with drug-like molecules

The fungal cell envelope, consisting of the cell wall and plasma membrane, is a dynamic structure crucial for cell shape, viability, pathogenicity, and the cell's ability to interact with and respond to its environment. Most antifungal drug development target components of the fungal plasma membrane and cell wall, thus understanding its composition and interactions with small molecules is vital for biomedical research and drug development. However, studying cell walls and membranes is challenging due to their high degree of complexity, their heterogeneous and dynamic structure and their sensitivity to environmental conditions. Our review provides a unique exploration of how biophysical techniques have advanced our understanding of the cell envelope's structure, its role in fungal pathogenicity, and drug resistance, which are critical issues for global health and food security. We highlight recent advances in microscopy and spectroscopy approaches, combined with analytical techniques and lipidomics, that have enabled detailed study of fungal cell walls and plasma membranes at unprecedented spatial and temporal resolutions. These studies have helped provide structural models of fungal cell walls and plasma membranes, including important differences between clinically relevant fungal species that are critical for antifungal drug development. Our review also summarises commonly used model membranes systems and discusses challenges and considerations in bridging gaps between simplified models and cellular systems, and why they are lacking compared to bacterial and mammalian systems and what is required to improve these systems.