Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria
文献类型：期刊论文
| 作者 | Yang, Anming8; Song, Junfeng8; Li, Jiaqi8; Li, Youzhi8; Bai, Silei8; Zhou, Cailing8; Wang, Min8; Zhou, Yu8; Wen, Kang8; Luo, Miaomiao8 |
| 刊名 | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
 |
| 出版日期 | 2024-07-09 |
| 页码 | 17 |
| ISSN号 | 0002-7863 |
| DOI | 10.1021/jacs.4c04749 |
| 通讯作者 | Feng, Xinxin(xinxin_feng@hnu.edu.cn) |
| 英文摘要 | Addressing the global challenge of bacterial resistance demands innovative approaches, among which multitargeting is a widely used strategy. Current strategies of multitargeting, typically achieved through drug combinations or single agents inherently aiming at multiple targets, face challenges such as stringent pharmacokinetic and pharmacodynamic requirements and cytotoxicity concerns. In this report, we propose a bacterial-specific global disruption approach as a vastly expanded multitargeting strategy that effectively disrupts bacterial subcellular organization. This effect is achieved through a pioneering chemical design of ligand-receptor interaction-induced aggregation of small molecules, i.e., DNA-induced aggregation of a diarginine peptidomimetic within bacterial cells. These intracellular aggregates display affinity toward various proteins and thus substantially interfere with essential bacterial functions and rupture bacterial cell membranes in an "inside-out" manner, leading to robust antibacterial activities and suppression of drug resistance. Additionally, biochemical analysis of macromolecule binding affinity, cytoplasmic localization patterns, and bacterial stress responses suggests that this bacterial-specific intracellular aggregation mechanism is fundamentally different from nonselective classic DNA or membrane binding mechanisms. These mechanistic distinctions, along with the peptidomimetic's selective permeation of bacterial membranes, contribute to its favorable biocompatibility and pharmacokinetic properties, enabling its in vivo antimicrobial efficacy in several animal models, including mice-based superficial wound models, subcutaneous abscess models, and septicemia infection models. These results highlight the great promise of ligand-receptor interaction-induced intracellular aggregation in achieving a globally disruptive multitargeting effect, thereby offering potential applications in the treatment of malignant cells, including pathogens, tumor cells, and infected tissues. |
| WOS关键词 | MEMBRANE CURVATURE ; DNA RECOGNITION ; SMALL MOLECULES ; TRANSCRIPTION ; PROTEIN ; ORGANIZATION ; MECHANISMS ; CYTOPLASM ; BINDING |
| 资助项目 | National Key Research and Development Program of China[2023YFD1800100] ; National Natural Science Foundation of China[22177031] ; National Natural Science Foundation of China[92163127] ; National Natural Science Foundation of China[82102415] ; National Natural Science Foundation of China[82304277] ; Natural Science Foundation of Hunan Province[2024JJ4007] ; Natural Science Foundation of Hunan Province[2022RC1107] ; Natural Science Foundation of Hunan Province[2024JJ2010] ; Natural Science Foundation of Changsha[kq2208050] ; Health and Medical Research Fund (HMRF), Hong Kong SAR[22210412] ; Independent Research Project of the College of Advanced Interdisciplinary Studies of NUDT[22-ZZKY-03] ; Institute of Chemical Biology and Nanomedicine, Hunan University |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001279996700001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/312559]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Feng, Xinxin |
| 作者单位 | 1.Hunan Univ, Coll Biol, Changsha 410082, Hunan, Peoples R China 2.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab Chiral Mol & Drug Discovery, State Key Lab Antiinfect Drug Discovery & Dev, Guangzhou 510006, Peoples R China 3.Natl Univ Def Technol, Nanhu Laser Lab, Changsha 410073, Peoples R China 4.Natl Univ Def Technol, Coll Adv Interdisciplinary Studies, Hunan Prov Key Lab Novel NanoOptoelectron Informat, Changsha 410073, Hunan, Peoples R China 5.Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, State Key Lab Chem Biol & Drug Discovery, Hong Kong 999077, Peoples R China 6.Xuzhou Med Univ, Sch Med Technol, Xuzhou 221004, Jiangsu, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 8.Hunan Univ, Coll Chem & Chem Engn, Hunan Prov Key Lab Biomacromolecular Chem Biol, State Key Lab Chemo Biosensing & Chemometr, Changsha 410082, Hunan, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yang, Anming,Song, Junfeng,Li, Jiaqi,et al. Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2024:17. |
| APA | Yang, Anming.,Song, Junfeng.,Li, Jiaqi.,Li, Youzhi.,Bai, Silei.,...&Feng, Xinxin.(2024).Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,17. |
| MLA | Yang, Anming,et al."Ligand-Receptor Interaction-Induced Intracellular Phase Separation: A Global Disruption Strategy for Resistance-Free Lethality of Pathogenic Bacteria".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2024):17. |
入库方式： OAI收割
来源：上海药物研究所
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