On March 20, 2025, Prof. Shang Zhuo from the School of Pharmaceutical Sciences, Shandong University, in collaboration with Prof. Wang Zongqiang from the National Key Laboratory of Multi-Target Natural Drugs at China Pharmaceutical University, published a research article titled “A Polyene Macrolide Targeting Phospholipids in the Fungal Cell Membrane” in Nature. This study has gained widespread attention and featured in Nature, Science Magazine, Chemical & Engineering News, and other major media. The research addresses the growing global crisis of drug-resistant fungal infections by discovering mandimycin, a novel antifungal candidate with a unique mechanism of action, through microbial genome mining. Prof. Wang Zongqiang and Prof. Shang Zhuo is the corresponding author of this paper.

Drug-resistant fungal infections pose a severe public health threat, with mortality rates reaching 30%-80%. Traditional antifungal drugs are limited by toxicity and rapid resistance development, prompting the WHO to call for novel antifungal treatments. In response, researchers leveraged microbial genome mining to discover Mandimycin, a unique polyene macrolide antibiotic targeting fungal cell membrane phospholipids. Identified from a database of 316,000 Streptomyces genomes, Mandimycin exhibits broad-spectrum, high-efficacy antifungal activity, including against multidrug-resistant Candida auris, with no resistance observed in the lab. Unlike traditional polyenemacrolide antibiotics that target sterols, Mandimycin disrupts fungal membranes by binding multiple phospholipids, offering a novel mechanism of action. Additionally, across various mouse infection models, it demonstrates comparable efficacy in eliminating fungal infections, reduced renal toxicity, and a 9,700-fold increase in water solubility compared to Amphotericin B. This discovery highlights the potential of evolution-based drug discovery and paves the way for Mandimycin’s clinical development as a next-generation antifungal.

This research was supported by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Department of Science and Technology of Shandong Province, and the Cheeloo Young Scholars Program of Shandong University.