一种合成的噬菌体-肽偶联物作为铜绿假单胞菌感染的有效抗菌剂

IF 10.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yanxi Yang, , , Shelby Vexler, , , Maria C. Jordan, , , Serena Abbondante, , , Dayeon Kang, , , Huan Peng, , , Michaela Marshall, , , Bita V. Naini, , , Saumya Jain, , , Yei-Chen Lai, , , Nasim Annabi, , , Kenneth P. Roos, , , Eric Pearlman, , and , Irene A. Chen*, 
{"title":"一种合成的噬菌体-肽偶联物作为铜绿假单胞菌感染的有效抗菌剂","authors":"Yanxi Yang,&nbsp;, ,&nbsp;Shelby Vexler,&nbsp;, ,&nbsp;Maria C. Jordan,&nbsp;, ,&nbsp;Serena Abbondante,&nbsp;, ,&nbsp;Dayeon Kang,&nbsp;, ,&nbsp;Huan Peng,&nbsp;, ,&nbsp;Michaela Marshall,&nbsp;, ,&nbsp;Bita V. Naini,&nbsp;, ,&nbsp;Saumya Jain,&nbsp;, ,&nbsp;Yei-Chen Lai,&nbsp;, ,&nbsp;Nasim Annabi,&nbsp;, ,&nbsp;Kenneth P. Roos,&nbsp;, ,&nbsp;Eric Pearlman,&nbsp;, and ,&nbsp;Irene A. Chen*,&nbsp;","doi":"10.1021/acscentsci.5c00562","DOIUrl":null,"url":null,"abstract":"<p >Antibiotic resistance among Gram-negative organisms is a major challenge. Some molecules, including antimicrobial peptides such as polymyxin B (PMB), are antibacterial but toxic due to low specificity, causing poor clinical utility. Drug delivery to bacterial cells using a biocompatible nanomaterial is a possible approach to securing such drugs. We engineered a nonlytic phage to recognize the lipopolysaccharide of Gram-negative bacteria and cross-linked thousands of peptides per virion, making “PMB-M13<sup>αLPS</sup>”. PMB-M13<sup>αLPS</sup> reduced the minimum inhibitory concentration <i>in vitro</i> by ∼2 orders of magnitude across multiple pathogen strains. Immunocompetent mice with multidrug-resistant <i>P. aeruginosa</i> pneumonia or corneal infection were effectively treated by PMB-M13<sup>αLPS</sup>, which showed potency ∼2 orders of magnitude greater <i>in vivo</i> compared to that of PMB. PMB-M13<sup>αLPS</sup> was well-tolerated, with no toxic effects. Conjugates of antimicrobial peptides and synthetic phages combine engineerable targeting with large payload capacity, improving potency and therapeutic index for otherwise toxic molecules.</p><p >A phage-peptide conjugate delivers an effective but toxic peptide specifically to bacterial cells. The conjugate treated mouse models of infection safely, showing how to increase clinical utility.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 9","pages":"1715–1735"},"PeriodicalIF":10.4000,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00562","citationCount":"0","resultStr":"{\"title\":\"A Synthetic Phage-Peptide Conjugate as a Potent Antibacterial Agent for Pseudomonas aeruginosa Infections\",\"authors\":\"Yanxi Yang,&nbsp;, ,&nbsp;Shelby Vexler,&nbsp;, ,&nbsp;Maria C. Jordan,&nbsp;, ,&nbsp;Serena Abbondante,&nbsp;, ,&nbsp;Dayeon Kang,&nbsp;, ,&nbsp;Huan Peng,&nbsp;, ,&nbsp;Michaela Marshall,&nbsp;, ,&nbsp;Bita V. Naini,&nbsp;, ,&nbsp;Saumya Jain,&nbsp;, ,&nbsp;Yei-Chen Lai,&nbsp;, ,&nbsp;Nasim Annabi,&nbsp;, ,&nbsp;Kenneth P. Roos,&nbsp;, ,&nbsp;Eric Pearlman,&nbsp;, and ,&nbsp;Irene A. Chen*,&nbsp;\",\"doi\":\"10.1021/acscentsci.5c00562\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Antibiotic resistance among Gram-negative organisms is a major challenge. Some molecules, including antimicrobial peptides such as polymyxin B (PMB), are antibacterial but toxic due to low specificity, causing poor clinical utility. Drug delivery to bacterial cells using a biocompatible nanomaterial is a possible approach to securing such drugs. We engineered a nonlytic phage to recognize the lipopolysaccharide of Gram-negative bacteria and cross-linked thousands of peptides per virion, making “PMB-M13<sup>αLPS</sup>”. PMB-M13<sup>αLPS</sup> reduced the minimum inhibitory concentration <i>in vitro</i> by ∼2 orders of magnitude across multiple pathogen strains. Immunocompetent mice with multidrug-resistant <i>P. aeruginosa</i> pneumonia or corneal infection were effectively treated by PMB-M13<sup>αLPS</sup>, which showed potency ∼2 orders of magnitude greater <i>in vivo</i> compared to that of PMB. PMB-M13<sup>αLPS</sup> was well-tolerated, with no toxic effects. Conjugates of antimicrobial peptides and synthetic phages combine engineerable targeting with large payload capacity, improving potency and therapeutic index for otherwise toxic molecules.</p><p >A phage-peptide conjugate delivers an effective but toxic peptide specifically to bacterial cells. The conjugate treated mouse models of infection safely, showing how to increase clinical utility.</p>\",\"PeriodicalId\":10,\"journal\":{\"name\":\"ACS Central Science\",\"volume\":\"11 9\",\"pages\":\"1715–1735\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2025-07-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00562\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Central Science\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acscentsci.5c00562\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscentsci.5c00562","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

摘要

革兰氏阴性菌的抗生素耐药性是一项重大挑战。一些分子,包括抗菌肽如多粘菌素B (polymyxin B, PMB),具有抗菌作用,但由于特异性较低而具有毒性,导致临床应用效果不佳。使用生物相容性纳米材料将药物输送到细菌细胞是一种可能的方法来保护这类药物。我们设计了一种非裂解噬菌体来识别革兰氏阴性菌的脂多糖,并在每个病毒粒子中交联数千个肽,制成“PMB-M13αLPS”。PMB-M13αLPS对多种病原菌的体外最低抑菌浓度降低了~ 2个数量级。PMB- m13 α lps可有效治疗耐多药铜绿假单胞菌肺炎或角膜感染的免疫活性小鼠,其体内效力比PMB高2个数量级。PMB-M13αLPS耐受良好,无毒性作用。抗菌肽缀合物和合成噬菌体结合了可工程靶向和大载荷能力,提高了对其他有毒分子的效力和治疗指数。噬菌体-肽缀合物可向细菌细胞提供有效但有毒的肽。该结合物对小鼠感染模型的治疗是安全的,显示了如何增加临床效用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Synthetic Phage-Peptide Conjugate as a Potent Antibacterial Agent for Pseudomonas aeruginosa Infections

Antibiotic resistance among Gram-negative organisms is a major challenge. Some molecules, including antimicrobial peptides such as polymyxin B (PMB), are antibacterial but toxic due to low specificity, causing poor clinical utility. Drug delivery to bacterial cells using a biocompatible nanomaterial is a possible approach to securing such drugs. We engineered a nonlytic phage to recognize the lipopolysaccharide of Gram-negative bacteria and cross-linked thousands of peptides per virion, making “PMB-M13αLPS”. PMB-M13αLPS reduced the minimum inhibitory concentration in vitro by ∼2 orders of magnitude across multiple pathogen strains. Immunocompetent mice with multidrug-resistant P. aeruginosa pneumonia or corneal infection were effectively treated by PMB-M13αLPS, which showed potency ∼2 orders of magnitude greater in vivo compared to that of PMB. PMB-M13αLPS was well-tolerated, with no toxic effects. Conjugates of antimicrobial peptides and synthetic phages combine engineerable targeting with large payload capacity, improving potency and therapeutic index for otherwise toxic molecules.

A phage-peptide conjugate delivers an effective but toxic peptide specifically to bacterial cells. The conjugate treated mouse models of infection safely, showing how to increase clinical utility.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
ACS Central Science
ACS Central Science Chemical Engineering-General Chemical Engineering
CiteScore
25.50
自引率
0.50%
发文量
194
审稿时长
10 weeks
期刊介绍: ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信