Progress in research and development of new sulfonium modified glycopeptide antibiotics by Shanghai Institute of medicine, Chinese Academy of Sciences

At present, 700000 people die of drug-resistant bacteria infection every year in the world Vancomycin resistant Staphylococcus aureus (visa, VRSA) and Enterococcus (VRE) are listed as 12 important drug-resistant bacteria in need of new antibiotics by the World Health Organization (who) The research team of Huang Wei, LAN Lefu and Gong Likun from Shanghai Institute of pharmaceutical research, Chinese Academy of Sciences actively developed new glycopeptide antibiotics in response to the major clinical needs of drug-resistant bacteria infection In the early research, the glycolipid modification strategy and pyrophosphate targeting strategy were used to develop a safer and more effective candidate drug-resistant bacteria sm-v-61 Recently, the research team designed and synthesized a series of novel glycopeptide antibiotic analogues by introducing sulfonium fragments into vancomycin's structural framework at four modified sites, namely vancomycin, m-diphenol, C-terminal and N-terminal In vitro Pharmacodynamics Study, this strategy has been proved to effectively improve the activity of vancomycin resistant bacteria, up to 2048 times of vancomycin This strategy is effective not only for VRE, which is highly resistant to vancomycin, but also for some Gram-negative bacteria Studies on the mechanism of action show that the sulfonium modified glycopeptide antibiotics can effectively increase the permeability of bacterial cell membrane, cause depolarization, destroy the integrity of cell membrane, and effectively improve the activity of anti drug resistant bacteria In vivo pharmacokinetic studies show that sulfonium glycopeptide antibiotics can effectively improve the drug exposure (AUC), while maintaining a moderate in vivo clearance rate and avoiding accumulated toxicity In the nephrotoxicity experiment, sulfonium derivatives have higher safety than those modified by thioether or quaternary ammonium ions On the whole, the structure optimization strategy based on sulfonium ion modification is effective and safe, with good drug properties, which is one of the important strategies underestimated in pharmaceutical chemistry This work not only provides a new structure of glycopeptide antibiotics for the resistance to multidrug-resistant bacteria infection, but also provides a novel sulfonium modified application for the strategy of drug chemical structure transformation This research work was published in angelw Chem Int ed (DOI: 10.1002 / anie 201902210) The first author of this paper is Guan Dongliang, a doctoral candidate from Shanghai Institute of medicine, Chinese Academy of Sciences, and Chen Feifei, an associate researcher This project was supported by NSFC and national major new drug creation project.