Targeting lipopolysaccharides in gram-negative sepsis: therapeutic advances and challenges.

IF 3.9 4区 医学 Q1 PHARMACOLOGY & PHARMACY
Oluwakorede Akele, Freeha Rana, Sudeep Acharya, David LeDoux, Michel Chalhoub
{"title":"Targeting lipopolysaccharides in gram-negative sepsis: therapeutic advances and challenges.","authors":"Oluwakorede Akele, Freeha Rana, Sudeep Acharya, David LeDoux, Michel Chalhoub","doi":"10.1080/1061186X.2025.2546487","DOIUrl":null,"url":null,"abstract":"<p><p>Gram-negative bacterial sepsis remains a major global health threat, exacerbated by rising antimicrobial resistance and limited efficacy of current therapies. Central to its pathogenesis is lipopolysaccharide (LPS), a potent endotoxin that triggers overwhelming inflammation and organ dysfunction. This review critically evaluates emerging therapies targeting LPS in sepsis. Key strategies include antibiotics disrupting LPS biosynthesis and transport (e.g. zosurabalpin, darobactin), monoclonal and bispecific antibodies, extracorporeal endotoxin removal devices, and novel agents like LpxC inhibitors and nanotechnology-based platforms. Despite promising preclinical and early clinical data, translation to practice is limited by pharmacokinetic challenges, toxicity, resistance mechanisms, and inadequate patient stratification. Anti-LPS antibodies and polymyxins have shown selective benefits but face setbacks in broader trials. Nanotherapeutics and targeted filtration systems like oXiris<sup>®</sup> and Alteco<sup>®</sup> offer adjunctive potential but require validation through randomised studies. The complexity of LPS biology and sepsis heterogeneity demonstrates the need for precision medicine approaches and biomarker-guided interventions. Addressing scalability, regulatory hurdles, and cost-effectiveness will be critical to integrating LPS-targeted therapies into standard sepsis care. This review outlines a translational roadmap to harness these innovations and improve outcomes in Gram-negative sepsis.</p>","PeriodicalId":15573,"journal":{"name":"Journal of Drug Targeting","volume":" ","pages":"1-13"},"PeriodicalIF":3.9000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Drug Targeting","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/1061186X.2025.2546487","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Gram-negative bacterial sepsis remains a major global health threat, exacerbated by rising antimicrobial resistance and limited efficacy of current therapies. Central to its pathogenesis is lipopolysaccharide (LPS), a potent endotoxin that triggers overwhelming inflammation and organ dysfunction. This review critically evaluates emerging therapies targeting LPS in sepsis. Key strategies include antibiotics disrupting LPS biosynthesis and transport (e.g. zosurabalpin, darobactin), monoclonal and bispecific antibodies, extracorporeal endotoxin removal devices, and novel agents like LpxC inhibitors and nanotechnology-based platforms. Despite promising preclinical and early clinical data, translation to practice is limited by pharmacokinetic challenges, toxicity, resistance mechanisms, and inadequate patient stratification. Anti-LPS antibodies and polymyxins have shown selective benefits but face setbacks in broader trials. Nanotherapeutics and targeted filtration systems like oXiris® and Alteco® offer adjunctive potential but require validation through randomised studies. The complexity of LPS biology and sepsis heterogeneity demonstrates the need for precision medicine approaches and biomarker-guided interventions. Addressing scalability, regulatory hurdles, and cost-effectiveness will be critical to integrating LPS-targeted therapies into standard sepsis care. This review outlines a translational roadmap to harness these innovations and improve outcomes in Gram-negative sepsis.

靶向脂多糖治疗革兰氏阴性脓毒症:治疗进展和挑战。
革兰氏阴性细菌性败血症仍然是一个主要的全球健康威胁,由于抗菌素耐药性上升和现有治疗方法疗效有限而加剧。其发病机制的核心是脂多糖(LPS),这是一种强有力的内毒素,可引发压倒性的炎症和器官功能障碍。这篇综述批判性地评价了针对LPS治疗败血症的新疗法。关键策略包括破坏LPS生物合成和运输的抗生素(例如zosurabalpin, darobactin),单克隆和双特异性抗体,体外内毒素去除装置,以及LpxC抑制剂和基于纳米技术的平台等新型药物。尽管临床前和早期临床数据很有希望,但转化为实践受到药代动力学挑战、毒性、耐药机制和患者分层不足的限制。抗lps抗体和多粘菌素已经显示出选择性的益处,但在更广泛的试验中面临挫折。纳米疗法和靶向过滤系统(如oXiris®和Alteco®)具有辅助潜力,但需要通过随机研究进行验证。LPS生物学的复杂性和脓毒症的异质性强调了精确医学方法和生物标志物引导干预的必要性。解决可扩展性、监管障碍和成本效益将是将lps靶向治疗纳入标准败血症治疗的关键。这篇综述概述了利用这些创新和改善革兰氏阴性脓毒症结局的转化路线图。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.10
自引率
0.00%
发文量
165
审稿时长
2 months
期刊介绍: Journal of Drug Targeting publishes papers and reviews on all aspects of drug delivery and targeting for molecular and macromolecular drugs including the design and characterization of carrier systems (whether colloidal, protein or polymeric) for both vitro and/or in vivo applications of these drugs. Papers are not restricted to drugs delivered by way of a carrier, but also include studies on molecular and macromolecular drugs that are designed to target specific cellular or extra-cellular molecules. As such the journal publishes results on the activity, delivery and targeting of therapeutic peptides/proteins and nucleic acids including genes/plasmid DNA, gene silencing nucleic acids (e.g. small interfering (si)RNA, antisense oligonucleotides, ribozymes, DNAzymes), as well as aptamers, mononucleotides and monoclonal antibodies and their conjugates. The diagnostic application of targeting technologies as well as targeted delivery of diagnostic and imaging agents also fall within the scope of the journal. In addition, papers are sought on self-regulating systems, systems responsive to their environment and to external stimuli and those that can produce programmed, pulsed and otherwise complex delivery patterns.
×
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