A Rationally Designed Sulfonium Lipoglycopeptide with Micelles Self-Assembly to Combat Multidrug Resistance via Dual Enhanced Cell Wall-Membrane Inhibition and T7SS Proteins Downregulation
文献类型：期刊论文
| 作者 | Xie, Yuanyuan2,3,4; Wang, Xiaowen2,3; Li, Fang2; Chen, Zhifu5; Li, Qun2; Liu, Shuhui2; Zhang, Jingwen6; Wang, Hui1; Wu, Zhenyong2,3,7; Zhang, Jinyong5 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2025-04-08 |
| 卷号 | 147期号:15页码:12587-12603 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.4c18630 |
| 通讯作者 | Zhang, Jinyong(zhangjy198217@126.com) ; Guan, Dongliang(guandongliang@simm.ac.cn) |
| 英文摘要 | Multidrug-resistant Gram-positive superbugs pose a significant menace to global public health, urgently demanding the advent of novel antibiotics. In this study, three biphenyl sulfonium lipoglycopeptides derived from vancomycin were rationally designed and synthesized to combat such resistance. Among them, the most promising derivative, BD-V-2, exhibited outstanding in vitro activity against a diverse array of refractory strains. Notably, in two highly challenging lethal sepsis models induced by MRSA and VREm (vanA), BD-V-2 achieved complete protection of the infected mice with remarkably low single-dose administrations of merely 7 and 2.5 mg/kg, respectively, vividly demonstrating its potent in vivo efficacy. Furthermore, its in vivo pharmacokinetic profile and toxicity assessment indicated favorable druggability. Interestingly, BD-V-2 was found to impart a novel self-assembly property into micelles. In addition, independent and synergistic mechanisms of action targeting the bacterial membrane, via phosphatidylglycerol (PG) interaction, and cell wall, via two more binding sites on lipid II, respectively, interpeptide bridge and pyrophosphate motif, were elucidated. Astonishingly, BD-V-2 was capable of significantly downregulating the expression of the type VII secretion system proteins, uncovering an unprecedented antivirulence mechanism for glycopeptide antibiotics. Collectively, these findings unraveled the hitherto unknown roles of the sulfonium strategy and established BD-V-2 as a highly prospective candidate for future pharmaceutical development. |
| WOS关键词 | ALA-D-ALA ; STAPHYLOCOCCUS-AUREUS ; REENGINEERING VANCOMYCIN ; BINDING ; BIOSYNTHESIS ; ORITAVANCIN ; BACTERIA ; ANALOGS ; PATHOGENESIS ; DERIVATIVES |
| 资助项目 | National Natural Science Foundation of China[82304272] ; National Natural Science Foundation of China[32170938] ; National Natural Science Foundation of China[32371283] ; National Natural Science Foundation of China[2023705] ; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Shanghai Postdoctoral Excellence Program[GZC20232847] ; Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation[202203060917] ; Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation[Efm-HS-vb02] ; Shandong Province Medical and Health Science and Technology Development Project ; Pharmaceutical Analysis and Quality Research Platform of Bohai Rim Advanced Research Institute for Drug Discovery ; Yantai Institute of Coastal Zone Research |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001461929100001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316962]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhang, Jinyong; Guan, Dongliang |
| 作者单位 | 1.Nanjing Cantech Microbial Technol Co Ltd, Nanjing 211100, Peoples R China 2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China 5.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China 6.Shandong Second Med Univ, Clin Res Ctr, Dept Endocrinol & Metab, Affiliated Hosp,Shandong Prov Key Med & Hlth Disci, Weifang 261031, Peoples R China 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Yuanyuan,Wang, Xiaowen,Li, Fang,et al. A Rationally Designed Sulfonium Lipoglycopeptide with Micelles Self-Assembly to Combat Multidrug Resistance via Dual Enhanced Cell Wall-Membrane Inhibition and T7SS Proteins Downregulation[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(15):12587-12603. |
| APA | Xie, Yuanyuan.,Wang, Xiaowen.,Li, Fang.,Chen, Zhifu.,Li, Qun.,...&Guan, Dongliang.(2025).A Rationally Designed Sulfonium Lipoglycopeptide with Micelles Self-Assembly to Combat Multidrug Resistance via Dual Enhanced Cell Wall-Membrane Inhibition and T7SS Proteins Downregulation.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(15),12587-12603. |
| MLA | Xie, Yuanyuan,et al."A Rationally Designed Sulfonium Lipoglycopeptide with Micelles Self-Assembly to Combat Multidrug Resistance via Dual Enhanced Cell Wall-Membrane Inhibition and T7SS Proteins Downregulation".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.15(2025):12587-12603. |
入库方式： OAI收割
来源：上海药物研究所
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