Novel Rationally Designed Lipopeptides Derived from Bacitracin: Combating Multidrug Resistance and Evading Bacitracin Resistance via Potentiated Cell Wall and Membrane Inhibitions
文献类型：期刊论文
| 作者 | Cheng, Sijie4,5; Liao, Jingwen3; Chen, Zhifu3; Li, Fang4; Zhu, Yanping5; Zhang, Jinyong3; Guan, Dongliang1,2,4,5 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-08-14 |
| 卷号 | 68期号:15页码:16410-16426 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c01285 |
| 通讯作者 | Zhang, Jinyong(zhangjy198217@126.com) ; Guan, Dongliang(dlguan@baridd.ac.cn) |
| 英文摘要 | The escalating threat posed by multidrug-resistant bacteria underscores the urgent need for novel antibiotics. Bacitracin, with its unique undecaprenyl pyrophosphate-targeting mechanism, serves as an ideal template for structural optimization. Herein, we developed a site-selective modification strategy targeting the 7-ornithine amino group, a critical yet underexplored residue in bacitracin. This approach revitalized bacitracin's therapeutic potential against multidrug-resistant pathogens, achieving even up to 256-fold improved activity against methicillin-, vancomycin-, and daptomycin-resistant strains while systematically establishing previously unreported SAR at this locus. The lead compound, Bac-51, incorporating an optimized trifluoromethyl biphenyl moiety, demonstrated superior in vitro potency, favorable safety/pharmacokinetic profiles, and single-dose efficacy in a lethal MRSA sepsis murine model. Mechanistic studies revealed it has a dual mode of action: enhanced peptidoglycan biosynthesis inhibition and membrane-disrupting activity, which minimized resistance development and exhibited continuous efficacy against acquired bacitracin-resistant strains. Collectively, Bac-51 represents a next-generation bacitracin analog as a promising candidate for combating multidrug-resistant Gram-positive infections. |
| WOS关键词 | GLYCOPEPTIDE ANTIBIOTICS ; STAPHYLOCOCCUS-AUREUS ; VANCOMYCIN ; BIOSYNTHESIS ; BINDING |
| 资助项目 | National Natural Science Foundation of China[82304272] ; National Natural Science Foundation of China[32170938] ; National Natural Science Foundation of China[ZR2024QH641] ; Shandong Province Science Foundation for Youths ; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001542687900001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321171]  |
| 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.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China 4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 5.Yantai Univ, Key Lab Mol Pharmacol & Drug Evaluat, Sch Pharm, Minist Educ, Yantai 264005, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cheng, Sijie,Liao, Jingwen,Chen, Zhifu,et al. Novel Rationally Designed Lipopeptides Derived from Bacitracin: Combating Multidrug Resistance and Evading Bacitracin Resistance via Potentiated Cell Wall and Membrane Inhibitions[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(15):16410-16426. |
| APA | Cheng, Sijie.,Liao, Jingwen.,Chen, Zhifu.,Li, Fang.,Zhu, Yanping.,...&Guan, Dongliang.(2025).Novel Rationally Designed Lipopeptides Derived from Bacitracin: Combating Multidrug Resistance and Evading Bacitracin Resistance via Potentiated Cell Wall and Membrane Inhibitions.JOURNAL OF MEDICINAL CHEMISTRY,68(15),16410-16426. |
| MLA | Cheng, Sijie,et al."Novel Rationally Designed Lipopeptides Derived from Bacitracin: Combating Multidrug Resistance and Evading Bacitracin Resistance via Potentiated Cell Wall and Membrane Inhibitions".JOURNAL OF MEDICINAL CHEMISTRY 68.15(2025):16410-16426. |
入库方式： OAI收割
来源：上海药物研究所
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