On March 22nd, the research article entitled "Structural and mechanistic insights into fungal β-1,3-glucan synthase FKS1" was published in the internationally renowned academic journal Nature. The article was authored by Yu Hongjun and Zhang Min's team from the School of Basic Medicine of Huazhong University of Science and Technology, in collaboration with Liu Xiaotian from the Southern University of Science and Technology. This research solves the mystery of fungal cell wall β-1,3-glucan synthesis, an important target of antifungal drugs. It is of great scientific significance for dealing with the clinical problem of invasive fungal infections.
Invasive fungal infections, which are common in high-risk populations, such as the immunocompromised population, organ transplant recipients, and patients with severe COVID-19, cause over 1.5 million deaths every year. However, the treatment of this serious disease is facing major challenges, including limited classes of drugs, side effects of drugs, and the emerging drug-resistant strains. Therefore, it is of urgent demand to develop new antifungal drugs. β-1,3-glucan is the core polysaccharide component unique to the fungal cell wall, and its synthesis pathway is a key target for developing antifungal drugs. Successful targeted drugs include the widely used echinocandin class of first-line drugs and the recently approved new drugs ibrexafungerp and rezafungin. However, for a long time, there has been a lack of understanding of the synthesis mechanism of β-1,3-glucan in the fungal cell wall and related drug resistance, which seriously hinder the development of new drugs in this field.
To address the above problems, the research team combined multiple methods and forcefully demonstrated that FKS1 is the specific synthase for fungal cell wall β-1,3-glucan. Based on this, a practical radiolabel-free assay system for FKS1 was developed, which has application potential in establishing an efficient drug screening system. Furthermore, the research team solved the cryoEM structure of FKS1 and identified two key functional regions of FKS1, including the catalytic site of the enzyme at the membrane-cytoplasm interface and a semi-closed glucan translocation path spanning the membrane bilayer, thus figuring out the molecular basis of glucan synthesis by FKS1. This mechanism is highly conserved in prominent fungal pathogens and has important significance for the development of broad-spectrum antifungal drugs.
To explore the mechanism of drug resistance, the researcher team revealed the spatial distribution and characteristics of resistance-related hotspot regions and confirmed that mutations in these sites would significantly reduce drug sensitivity of FKS1. They ultimately worked out the structure of FKS1-S643P, one of the most frequently observed echinocandin-resistant mutations in clinical practice. The structure revealed altered lipid arrangements, suggesting a unique molecular mechanism of drug resistance.
In conclusion, the research has advanced the mechanistic understanding of β-1,3-glucan synthesis in fungal cell walls. It reveals the molecular basis of resistance to widely prescribed antifungal drug echinocandin. These insights and assay methods in this research are valuable for promoting the development of new antifungal drugs and helpful for solving the clinical problem of invasive fungal infections.
Profs. Yu Hongjun, Zhang Min and Liu Xiaotian are the co-corresponding authors of this article. Hu Xinlin and Yang Ping from the School of Basic Medicine of HUST are co-first authors. This research has been supported by the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, Program for HUST Academic Frontier Youth Team and ShenZhen Talent Program.
This article represents another research breakthrough in the field of antifungal drug targets by the team of Profs. Yu Hongjun and Zhang Min from the School of Basic Medicine, following their previous article “Structures and mechanism of chitin synthase and its inhibition by antifungal drug Nikkomycin Z” (Cell Discovery. 2022;8(1):129.). The team has long been engaging in the mechanistic study of disease-related proteins, especially the mechanism and intervention of eukaryotic glycosylation and their therapeutic applications. Their research findings have been published in several internationally renowned journals, such as Nature, Cell, Nature Chemical Biology, PNAS, and Nature Communications.
Source: School of Basic Medicine
Edited by: Chang Wen, Peng Yumeng