On March 20, 2025, Prof. Wang Zongqiang's team from the State Key Laboratory of Natural Medicines, China Pharmaceutical University, together with Prof. Shang Zhuo from the School of Pharmaceutical Sciences of Shandong University, published a research paper online in the form of Article in the top international academic journal Nature, entitled A Polyene Macrolide Targeting Phospholipids in the Fungal Cell Membrane. In response to the serious problem of drug-resistant fungal infections around the world, the study mined and biosynthesized Mandimycin, the first polyene macrolide antifungal drug candidate with a brand new target, which breaks through the knowledge of a single mechanism of polyene natural products in recent decades and provides a breakthrough solution for clinical treatment. Qisen Deng and Yinchuan Li, PhD students from the State Key Laboratory of Natural Medicines, China Pharmaceutical University, are the co-first authors of the paper, Prof. Zongqiang Wang and Prof. Zhuo Shang are the co-corresponding authors, Prof. Zongqiang Wang is the last corresponding author, and China Pharmaceutical University is the first completion unit of the paper.
Antibiotic-resistant strains of bacteria are widespread in nature. Prof. Wang Zongqiang's team found that in order to maintain a competitive advantage in the natural environment, antibiotic-producing bacteria have evolved a strategy: to optimize the structure of antibiotics through molecular modification in order to combat drug-resistant bacteria. The research team built a database of 1.78 million biosynthetic gene clusters of microbial secondary metabolites based on this “theory of bacterial reverse evolution”, and rapidly targeted key biosynthetic gene clusters through bioinformatics-driven gene mining technology. Through combinatorial biosynthesis, Mandimycin, the first polyene macrolide antibiotic targeting a phospholipid molecule with broad-spectrum potency, innovative mechanism, and high safety profile, was finally obtained. This breakthrough discovery not only overturns the traditional knowledge of the mechanism of action of polyene macrolide antibiotics (targeting sterols), but also injects new momentum into the treatment of drug-resistant fungal infections, and provides a new paradigm for research and development to deal with the crisis of antibiotic resistance.Due to the unique structural features and novel targets, Mandimycin has great potential to become a new-generation antibiotic for the treatment of drug-resistant fungal infections in the clinic. Mandimycin has great potential to become a new generation of antibiotics against clinically resistant fungal infections. However, in view of the potential side effects associated with its phospholipid-targeting mechanism, the research team's next step will be to investigate its toxicological mechanism and comprehensively evaluate its clinical safety and efficacy.
This research was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Talent Start-up Fund of China Pharmaceutical University, and the Engineering Research Center for the Creation of New Anti-infective Drugs of the Ministry of Education. Prof. Zongqiang Wang was introduced to our university in 2022 as an emerging pharmaceutical leader of China Pharmaceutical University, and is currently a professor and doctoral supervisor of the National Key Laboratory of Multi-target Natural Drugs of China Pharmaceutical University, director of the Engineering Research Center for the Creation of Synthetic Biology of Anti-infective Microbial Drugs in Nanjing, and has been selected for the National Young Talent Program (Class A) and the Jiangsu Provincial Specially Appointed Professors. The group has long been committed to original anti-infective microbial drug discovery and drugability research, through the development of technical means that do not depend on the activity screening, the integrated use of synthetic biology, natural product chemistry, peptide chemistry and other technologies, mining from the microbial (macro-) genome with anti-infective activity of natural products, exploring the laws of biosynthesis of complex natural products, to explore the microbial origin of innovative drugs. In the past five years, Prof. Zongqiang Wang has published several papers in Nature, Science, Nat. Comm. and other journals as the first or corresponding author, and has led the development of two antibiotic candidates that have entered preclinical studies.
Original link: https://www.nature.com/articles/s41586-025-08678-9
