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 randomized studies. The complexity of LPS biology and sepsis heterogeneity underscores 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.

2024-12-13·ACS Infectious Diseases

In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens

Article

作者: Müller, Alison V. ; Sandargo, Birthe ; Deckarm, Selina ; Kany, Andreas M. ; Müller, Rolf ; Seyfert, Carsten E. ; Dubarry, Nelly ; Chacón Ortiz, María ; Fries, Franziska ; Vaddi, Swapna ; Bernecker, Steffen ; Porten, Christoph ; Stadler, Marc ; Bacqué, Eric ; Herrmann, Jennifer ; Große, Miriam

In recent years, naturally occurring darobactins have emerged as a promising compound class to combat infections caused by critical Gram-negative pathogens. In this study, we describe the in vivo evaluation of derivative D22, a non-natural biosynthetic darobactin analogue with significantly improved antibacterial activity. We found D22 to be active in vivo against key critical Gram-negative human pathogens, as demonstrated in murine models of Pseudomonas aeruginosa thigh infection, Escherichia coli peritonitis/sepsis, and urinary tract infection (UTI). Furthermore, we observed the restored survival of Acinetobacter baumannii-infected embryos in a zebrafish infection model. These in vivo proof-of-concept (PoC) in diverse models of infection against highly relevant pathogens, including drug-resistant isolates, highlight the versatility of darobactins in the treatment of bacterial infections and show superiority of D22 over the natural darobactin A. Together with a favorable safety profile, these findings pave the way for further optimization of the darobactin scaffold toward the development of a novel antibiotic.

2024-08-09·ACS Infectious Diseases

Exploring the Darobactin Class of Antibiotics: A Comprehensive Review from Discovery to Recent Advancements

Review

作者: Yarlagadda, Venkateswarlu ; Dutta, Akash ; Sharma, Peehu ; Dass, Dharam

The prevalence of antimicrobial resistance in Gram-negative bacteria poses a greater challenge due to their intrinsic resistance to many antibiotics. Recently, darobactins have emerged as a novel class of antibiotics originating from previously unexplored Gram-negative bacterial species such as Photorhabdus, Vibrio, Pseudoalteromonas and Yersinia. Darobactins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) class of antibiotics, exhibiting selective activity against Gram-negative bacteria. They target the β-barrel assembly machinery (BAM), which is crucial for the maturation and insertion of outer membrane proteins in Gram-negative bacteria. The dar operon in the producer's genome encodes for the synthesis of darobactins, which are characterized by a fused ring system connected via an alkyl-aryl ether linkage (C-O-C) and a C-C cross-link. The enzyme DarE, using the radical S-adenosyl-l-methionine (rSAM), facilitates the formation of these bonds. Biosynthetic manipulation of the darobactin gene cluster, along with its expression in a surrogate host, has enabled access to diverse darobactin analogues with variable antibiotic activities. Recently, two independent research groups successfully achieved the total synthesis of darobactin, employing Larock heteroannulation to construct the bicyclic structure. This paper presents a comprehensive review of darobactins, encompassing their discovery through to the most recent advancements.

项与 Darobactin 相关的新闻（医药）

2025-07-10

·生物谷

臭名昭著的“致癌物”竟摇身一变成为抗癌分子药物？！多项研究：常见于不新鲜坚果、谷物中的黄曲霉素，其天然产物或成为精准抗癌药物

黄曲霉素是一种由某些霉菌产生的毒素，长期以来因其强烈的致癌性和肝毒性而臭名昭著。它通常在储存不当的坚果、谷物和干果中被发现，特别是在温暖潮湿的环境中容易滋生。然而，科学研究有时会带来意想不到的发现。近日，一项发表在《自然·化学生物学》上的题为“A class of benzofuranoindoline-bearing heptacyclic fungal RiPPs with anticancer activities”的研究揭示了来自真菌的黄曲霉素类化合物的抗癌活性。这项来自宾夕法尼亚大学和莱斯大学等机构的研究，为从真菌资源中寻找新药打开了新的大门。RiPPs：天然产物的重要来源核糖体合成并经过翻译后修饰的肽类（RiPPs）是具有多种生物活性的天然产物的重要来源。虽然细菌中的RiPPs已经被广泛研究，但真菌中的这类化合物却鲜为人知。此次首次发现了一类结构独特的真菌RiPPs——黄曲霉素。这些化合物拥有一个苯并呋喃吲哚啉核心结构，并包含三个额外的大环，主要由六种真菌特有的DUF3328氧化酶组装而成。为了从曲霉属中筛选RiPP候选物，研究人员首先在十种不同的培养基中培养了12株曲霉属真菌，并利用超高效液相色谱-电喷雾/四极杆飞行时间串联质谱（LC-MS/MS）技术分析其代谢产物。随后通过全球天然产物社会分子网络（GNPS）构建分子网络图谱，发现了来自黄曲霉（Aspergillus flavus）和米曲霉（Aspergillus oryzae）的一个特殊分子簇，其质谱碎片显示出Ile（异亮氨酸）和Gly（甘氨酸）的存在迹象。研究人员进一步利用antiSMASH工具分析黄曲霉基因组，识别出一个可能的前体肽ApgA，其氨基酸序列与GNPS结果完全吻合。为了验证其作用，研究人员敲除了apgA基因，LC-MS结果显示该突变株完全失去了原本的四个主要化合物峰，从而确认这些化合物来源于ApgA。研究人员成功分离出四种新型真菌RiPPs，并将其命名为黄曲霉素 A-D（1-4）。通过一维和二维核磁共振（NMR）技术，他们解析了这些化合物的化学结构。图注：黄曲霉素的发现与合成初步生物活性测试显示，黄曲霉素并不具备明显的抗菌活性。但在针对多种人类癌细胞系（如白血病、肝癌、乳腺癌、宫颈癌）的测试中，研究人员发现了一个关键现象：化合物1和2因N端未修饰而无活性，而化合物3和4由于含有吡咯谷氨酸，在多种白血病细胞系（如Jurkat、Mino、Molm-14）中表现出显著的细胞毒性，IC₅₀值在0.34至2.3 µM之间，与临床上批准的抗白血病药物相当！受此启发，研究人员尝试对化合物2进行化学修饰，将其N端自由胺替换为不同长度的脂链。令人惊喜的是，一种名为2−L₆的衍生物（含有一个线性C11饱和脂肪酸链）的活性提升了超过100倍，IC₅₀值降至40–99 nM，与阿糖胞苷（cytarabine）和柔红霉素（daunorubicin）等临床常用药物相当！图注：CRISPR筛选揭示SLC46A3是黄曲霉素衍生物的转运蛋白为了弄清2−L₆是如何进入人体细胞的，研究人员在Jurkat细胞中进行了高通量CRISPR筛选，最终识别出SLC46A3蛋白作为2−L₆的关键转运载体。当敲除SLC46A3基因后，2−L₆的IC₅₀值上升了30倍，细胞内浓度下降了8倍，证明其确实在药物摄取过程中发挥了核心作用。研究表明，脂化的黄曲霉素主要通过内吞作用进入细胞，随后由溶酶体通过SLC46A3转运至细胞质中发挥作用。进一步实验还发现，这些化合物能够抑制微管蛋白聚合，这是细胞分裂过程中的关键步骤，因此推测这是其抗癌作用的主要机制。这项研究不仅揭示了一类全新的、具有强大抗癌潜力的真菌RiPPs，还系统解析了它们的生物合成途径、结构特征、转运机制和作用靶点。特别是SLC46A3转运体的发现，为理解多肽类药物如何进入人体细胞提供了重要线索，也为开发基于肽类的抗癌疗法奠定了坚实基础。随着越来越多的真菌资源被挖掘，类似黄曲霉素这样的天然产物有望成为下一代精准抗癌药物的重要来源。药物开发的前沿领域，潜力巨大但挑战重重此前，英国皇家化学会的期刊《天然产物报告》曾经发表了一篇综述文章，全面回顾了RiPPs在药物研发中的广阔前景，同时也指出了其走向临床应用所面临的多重障碍。该文强调RiPPs是一类具有高度生物活性、但尚未被充分挖掘的天然产物。RiPPs为应对日益严重的抗生素耐药问题提供了新希望，如达拉霉素和肉桂霉素靶向细菌细胞膜，Lexapeptide与Cacaoidin对MRSA等革兰氏阳性菌有效，Darobactin抑制革兰氏阴性菌的BamA蛋白。此外，RiPPs还展现出了抗真菌、抗病毒、抗寄生虫、抗癌及镇痛等多种生物活性。例如：抗真菌：Pinensin A和B是首个来自革兰氏阴性菌的抗真菌羊毛硫抗生素；Hymenamide A-C和E来自海洋海绵；Cyclothiazomycin B1通过结合几丁质抑制真菌生长；Humidimycin增强卡泊芬净的效果。抗病毒：Landornamide A抗沙粒病毒；Siamycins I、II、III抗HIV和HSV；Labyrinthopeptin A1阻止HIV和HSV进入宿主细胞；Duramycin防止埃博拉和登革热病毒感染。抗寄生虫：Thiostrepton靶向疟原虫蛋白酶体；Aeshna defensin和phormicin减少蚊子体内疟原虫发育；Balgacyclamides A-C和mollamide B对疟原虫和锥虫有效；kalata B1和cycloviolacin O14对抗人钩虫。抗癌：Siomycin A和thiostrepton抑制FoxM1转录因子；Wewakazole B和lissoclinamide 7对多种癌细胞有毒性；Microcin E492和nisin A/ZP诱导癌细胞凋亡；其他化合物干扰癌细胞关键信号通路或增强化疗效果。镇痛：Labyrinthopeptin A2和NAI-112在疼痛模型中有效；Conotoxins高效阻断神经钙通道；蜘蛛毒液肽psalmotoxin 1和Tx3-5以及响尾蛇毒液中的crotalphine具有显著镇痛作用。图注：RiPPs的抗菌活性此外，RiPPs还具备抗炎、降压、降糖及抗帕金森病等多种功能，并用于显微镜观察和癌症诊断的显影剂。这些特性使得RiPPs成为极具潜力的新型药物候选资源。然而，尽管RiPPs展现出巨大的治疗潜力，但真正进入市场的并不多。为什么RiPPs难以广泛应用于临床？限制RiPPs临床转化的主要原因在于其不良的ADME特性（吸收、分布、代谢、排泄）。RiPPs在临床应用中面临多重挑战，如口服生物利用度低、吸收困难、代谢稳定性差以及潜在毒性风险。多数肽类在胃酸和蛋白酶作用下易降解，难以口服；其大分子量违反“里宾斯基五规则”，不易穿透细胞膜；进入血液后又易被肝肾清除，半衰期短；尽管副作用较少，高剂量仍可能引发毒性反应，如Ziconotide可能导致中枢神经系统不良反应。然而，RiPPs因其结构稳定性和可工程化特性，仍被视为极具潜力的药物候选者。当前，科研人员正通过开发新型递送系统（如纳米颗粒、脂质体）、构建缓释材料、优化靶向输送策略，并结合基因工程技术改良RiPPs结构，推动其成为高效、安全的新一代治疗药物。小结真菌黄曲霉素抗癌作用的发现，标志着RiPPs正逐步成为新药开发的重要源泉，涵盖从抗生素到抗癌药等多个领域。随着对其生物合成机制、结构-活性关系以及递送系统的深入研究，这一类天然产物有望在未来为多种重大疾病提供创新疗法。未来的关键在于持续的技术创新与跨学科合作，以真正释放RiPPs的巨大潜能！参考文献：1.Nie, Q., Zhao, F., Yu, X. et al. A class of benzofuranoindoline-bearing heptacyclic fungal RiPPs with anticancer activities. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-01946-92.Pfeiffer, Isabel P-M., Maria-Paula Schröder, and Silja Mordhorst. "Opportunities and challenges of RiPP-based therapeutics." Natural Product Reports (2024).DOI: 10.1039/D3NP00057E撰文 | linwen编辑 | lcc部分文字来源于网络，本文仅用于分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！精彩推荐：1、体脂率多少的男/女性最具吸引力？三项科学研究揭露“完美身材”：男性体脂率13-14%+肩腰比1.57；女性完美身材则更为严格2、别再不舍得开空调！Nature和子刊：温度调低，不仅能抑制多种癌症生长，还能燃脂减肥，改善代谢和心血管健康3、24岁或就埋下痴呆隐患！性格不好还易“加速”脑萎缩！两项研究：首次在24-44岁健康个体中检出痴呆风险因素；性格对脑健康很重要4、“欠睡债”很严重！多项研究表明：通宵一晚脑龄暴涨1-2岁，连续缺觉三天身体+情绪状态会直线下降5、是「陪伴无价」or「钱能“买”到爱」？两项研究：在难过时，送低价小礼物比谈心更暖心，且爱与金钱在大脑中会激活同一批奖励中枢点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

临床研究微生物疗法

100 项与 Darobactin 相关的药物交易

登录后查看更多信息