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Please note this is a comparison between Version 1 by Johannes Müthing and Version 2 by Johannes Müthing.
Enterohemorrhagic肠出血 Escherichia coli性大肠杆菌 (EHEC) are是产志贺毒素 the human pathogenic subset of Shiga toxin (Stx)-producing(Stx) E. coli 大肠杆菌的人类致病亚群(STEC). 。EHEC are responsible for severe colon infections associated with life-threatening extraintestinal complications such as the hemolytic-uremic syndrome 负责与危及生命的肠外并发症相关的严重结肠感染，例如溶血性尿毒症综合征 (HUS) and neurological disturbances. Endothelial cells in various human organs are renowned targets of Stx, whereas the role of epithelial cells of colon and kidneys in the infection process has been and is still a matter of debate.和神经系统障碍。治疗主要依赖于支持性重症监护方案，用于 EHEC 相关肠道和潜在致命的肠外并发症。重要的是，在儿科和成人临床表现之间不一致的患者群体中会出现差异特征。与儿童相比，成人 EHEC-HUS 的特点是神经系统症状普遍存在，预后较差，该疾病因缺乏特定治疗而对重症监护管理和治疗仍构成公共威胁。
- EHEC
- glycolipids
- lipid rafts
- STEC
1. Application of Antibiotics or Not That’s the Question是否使用抗生素这是个问题
The由于担心通过增加 administration of antibiotics inStx 产生来触发 HUS [285、286、287]，在 EHEC infections was and remains controversial because of concerns about triggering HU感染中使用抗生素一直存在争议，并且仍然存在争议。S by increasing Stx production [1][2][3]. Stxs are由位于人字形前噬菌体基因组上的基因编码，某些抗生素会刺激它们的诱导，从而导致 encoded by genes located on genomes of lambdoid prophages and certain antibiotics stimulate their induction leading to enhanced production of Stxs [4].的产生增加 Although[ numerous288 studies have]。尽管许多研究报告说抗生素会增加疾病症状的严重程度并增加进展为 reported that antibiotics enhance the severity of disease symptoms and increase the risk of progression to HUS development, further corroborated by in vitro antibiotic studies using certain EHEC strains, others have reportedHUS 发展的风险，使用某些 EHEC 菌株的体外抗生素研究进一步证实了这一点，但其他人报告说抗生素没有任何作用，甚至可以减少EHEC 感染中 HUS 的发生率 [ that289 antibiotics, do290, not291 have, any292 effect, or293 can, even294 reduce, the295 rate, of296 HUS development]。目前的数据情况得出的结论是，感染 in EHEC infections [5][6][7][8][9][10][11][12]. The current data situation leads to the conclusion that the infectingEHEC 菌株、抗生素类型及其应用时机似乎显着影响 EHEC strain,感染患者中 the type of antibiotic, and the timing of its application appear to significantly affect the development of HUS in EHEC-infectedHUS 的发展 [ patients285 [1].]。
2. Development of Non-Antibiotic Therapeutics非抗生素疗法的发展
In recent近年来，已经开发了多种替代治疗方法和治疗干预措施，并在体外、动物模型和临床试验中进行了评估，以预防 years, a variety of alternative treatment approaches and therapeutic interventions has been developed and evaluated in vitro, in animal models and clinical trials for preventing EHEC-associatedEHEC 相关的 HUS [13][14].[ The297 majority, of298 possible]。大多数可能的非抗生素疗法已经或处于开发阶段，旨在中和 non-antibiotic therapeutics has been or is in the developmental stage aimed to neutralize Stx, toStx，防止毒素粘附，阻断受体生物合成，并干扰细胞内毒素的运输、加工和活性 [ prevent6 toxin adhesion, to156 block, receptor293 biosynthesis, and299 to, interfere300 trafficking, processing,301]。由于 and activiSty of the toxin within the cell [9][15][16][17][18][19]. x 诱导易感细胞分泌炎性细胞因子和趋化因子，从而导致 HUSince Stx induces the secretion of inflammatory cytokines and chemokines from susceptible cells that contribute to the pathogenesis of HUS, these compounds are useful indicators of disease activity as well as predictors of disease progression and candidates for an anti-inflammation therapy as an additional treatment regimen for severe的发病，因此这些化合物是疾病活动性的有用指标，也是疾病进展的预测指标，也是抗炎治疗的候选者，可作为治疗 HUS 的额外治疗方案。严重的 E. coli-associated大肠杆菌相关 HUS [20].[ 302 ]。
2.1.。鞘糖脂生物合成抑制剂和 Inhibitors of Glycosphingolipid Biosynthesis and Stx-Neutralizing GlycoconjugatesStx 中和糖缀合物
Ceramide is the hydrophobic神经酰胺是所有复杂的两亲性鞘糖脂 backbone of all complex amphipathic glycosphingolipids (GSLs). Its initial glycosylation forming glucosylceramide (GSL) 的疏水骨架。其初始糖基化形成葡糖神经酰胺 (GlcCer) is the first committed and rate-limiting step in the biosynthesis of GSLs with GlcCer core leading to the various GSL-families including the是 GSL 生物合成中的第一个承诺和限速步骤，GSL 核心导致包括 globo-series [21].系列在内的各种 AGSL number of系列 [ ceramide303 analogs]。许多神经酰胺类似物，例如经典的 such as classical D-PDMP and many others has been scrutinized in the past as potential inhibitors of 和许多其他类似物，过去已被仔细研究为 GlcCer synthase mainly合酶的潜在抑制剂，主要开发用于治疗称为底物减少疗法的人类脂质贮积病 [ developed304 for, the305 treatment, of306 human, lipid307 storage, diseases308]。传统和新型 named as substrate reduction therapy [22][23][24][25][26]. The capability of traditional and novel GlcCer synthase合酶抑制剂降低 inhibitors to reduce the cellular level of the Stx receptorStx 受体 Gb3Cer in various在各种细胞类型（包括人类上皮细胞和内皮细胞）中的细胞水平的能力 [ cell183 types, including309 human] epithelial and endothelial cells [27][28] and并通过这种方式阻止 to prevent the cytotoxic action toward this way Gb3Cer-truncated target cells has expedited an additional focus on the Stx receptorr 截短靶细胞的细胞毒性作用已加速另外关注 Stx 受体 Gb3Cer as therapeutic target in Stx-mediated HUS. An example of a newly developed 作为 Stx 介导的 HUS 的治疗靶点。新开发的 GlcCer-synthase inhibitor is the ceramide analog 合酶抑制剂的一个例子是神经酰胺类似物 Eliglustat [26],[ also308 primarily developed]，它也主要开发为 as an alternative approach to the enzyme replacement therapy of patients suffering from GSL storage diseasesGSL 贮积病患者的酶替代疗法的替代方法 [ [29], effectively protects human renal tubular epithelial cells from Stx-caused310]，由于降低细胞 cellular damage due to reducing the cellular Gb3Cer levels suggesting its potential as Stx protector [30][31]. The水平，有效保护人肾小管上皮细胞免受 Stx 引起的细胞损伤，这表明其作为 prevention of Gb3Cer-synthesis and neutralization of Stx-mediated cytotoxic action 保护剂的潜力 [ by311 the, ceramide312 analog]。神经酰胺类似物 C-9, shown for primary human renal epithelial cells in vitro and an in vivo animal HUS model in rats offer a further option for treatment of 预防 Gb3Cer 合成和中和 Stx 介导的细胞毒性作用，在体外和大鼠体内动物 HUS 模型中显示了原代人肾上皮细胞，为治疗 EHEC-HUS [32][33].提供了进一步的选择[ 255、313 ]。_
Aligned与脂质锚的两亲性 to the opposite site of an amphipathic GSL from the lipid anchor, modifications of the hydrophilic glycan represent a further approach to impede or prevent Stx binding. Such metabolic modification can easily be done and has been reported for feeding of in vitro propagated cells with 2-deoxy-D-glucose or 2-fluoro-2-deoxy-D-glucose revealing protective effects ofGSL 的相反位点对齐，亲水性聚糖的修饰代表了阻止或防止 Stx 结合的进一步方法。这种代谢修饰可以很容易地完成，并且据报道用于用 2-脱氧-D-葡萄糖或 2-氟-2-脱氧-D-葡萄糖喂养体外增殖的细胞，揭示了这两种化合物对 Stx 的保护作用 [ both314 compounds, against315 Stx [34][35]. ]。2-deoxy脱氧-D-glucose becomes incorporated into the carbohydrate moiety of GSLs and protects cells against 葡萄糖被掺入 GSL 的碳水化合物部分并保护细胞免受 Stxs [34],[ while314]，而 2-fluoro-2-deoxy-D-glucose inhibits抑制 GlcCer biosynthesis thereby reducing the cellular levels of GSLs as shown for various cell types including human brain microvascular endothelial cells. This glucose-modification is much more efficient in protecting cells against Stx when compared to 2-deoxy-D-glucose生物合成，从而降低 GSL 的细胞水平，如包括人脑微血管内皮细胞在内的各种细胞类型所示。与 2-脱氧-D-葡萄糖相比，这种葡萄糖修饰在保护细胞免受 [35]. FurSthermore,x the clinically侵害方面更有效 [ approved315 glucose-derivative]。此外，临床批准的葡萄糖衍生物 Miglustat has been shown being effective in human endothelial and epithelial cells to decrease the level of Stx receptor已被证明在人类内皮细胞和上皮细胞中有效降低 Stx 受体 Gb3Cer suggesting its application as a feasible strategy to protect kidney tissues from Stx-mediated kidney的水平，这表明其可作为保护肾组织免受 Stx 介导的肾损伤的可行策略[ injury316 [36].]。总的来说，列举的神经酰胺类似物和葡萄糖衍生物表明 Collectively, the enumerated ceramide analogs and glucose-derivatives suggest potential clinical applications for Stx-caused diseases. 引起的疾病的潜在临床应用。
Since由于肠毒性细菌的蛋白质毒素已被证明是药物开发的有吸引力的目标 protein[ toxins of300 enterotoxic bacteria have proven to be attractive targets for drug development [18][37], numerous317 therapeutic]，因此已经开发了许多基于聚糖受体 glycoconjugates based on Stx-specific analogs ofGb3 的 Stx 特异性类似物的治疗性糖缀合物 [ the297 glycan, receptor318 Gb3 have been developed [13][38]. ]。Synsorb Pk [ [39],319 ]、Starfish [40],[ 320 ]、Daisy [41],[ 321 ]、SUPER TWIGS [42][43],[322、323 polymeric acrylamide] 、聚合丙烯酰胺-Gb3 conjugates偶联物 [44],[ 324 ]、Gb3（聚糖）封装的金纳米粒子 (glycan)[ encapsulated325、326 gold]、新糖脂加标糖泡[ nanoparticles327 [45][46], neoglycolipid-spiked328] glycovesicles或在其表面表达 [47][48] or engineered probiotics expressing Gb3 analogs类似物的工程益生菌 on[ their329 surface] [49] are是糖结构的例子，它们是为中和 examples of glycoconstructs, developed for neutralization of Stxs as described而开发的，正如最近一篇很好且强烈推荐的综述 [ more297 precisely] in a nice and highly recommended recent review [13]. However, although effective in vitro, potential 中更准确地描述的那样。然而，虽然在体外有效，但潜在的 Stx-binding neutralizers have结合中和剂在体内失败，在临床试验中没有显示出任何益处，并且迄今为止它们都没有获得临床批准 [ failed191 in, vivo292 showing no benefit in clinical trials and none of them has received clinical approval to date [8][50].]。
2.2. Monoclonal Antibodies单克隆抗体
Despite尽管在产生中和人源化（嵌合）或人单克隆抗 a tremendous increase of knowledge has been gained with regard to the generation of neutralizing humanized (chimeric) or human monoclonal anti-Stx antibodies toStx 抗体以对抗 Stx 介导的疾病 [ combat330 Stx-mediated, diseases331 [51][52][53], so332 far] no monoclonal antibody against Stx1(a) or方面已经获得了巨大的知识，但迄今为止还没有针对 Stx1 的单克隆抗体（a ) 或 Stx2(a) has received已获得临床批准 [ clinical297 approval, [13][54].333 The broadly administered anti-C5 monoclonal antibody Eculizumab during the]。在 2011 outbreak of an 年德国爆发 O104:H4 EHEC strain in Germany gave an equally good outcome of treated versus untreated patients and pointed to an advantageous use, at least for severe cases [55]. Th菌株期间，广泛使用的抗 C5 单克隆抗体 Eculis anti-C5 complement blocker has obviozusly made the difference between favorable ormab 在接受治疗的患者与未接受治疗的患者中产生了同样好的结果，并指出了有利的用途，至少对于严重病例 [ detrimental334 outcome]。这种抗 [55][56].C5 The补体阻滞剂显然在有利或不利结果之间产生了差异 administration[334、335 ]。_ of在伴有神经系统受累的 Eculizumab in EHEC-associated HUS with neurological involvement indicated that early use of HEC 相关 HUS 中使用 Eculizumab appeared to improve neurological outcome, whereas late treatment seemed to show less benefit suggesting advantage of prophylactic 表明，早期使用 Eculizumab 似乎可以改善神经系统结果，而晚期治疗似乎显示的益处较少，这表明在出现神经系统症状之前预防性 Eculizumab therapy before治疗的优势 [ development336 of]。因此，用依库珠单抗治疗 neurological symptoms [57]. Thus, treatment of EHEC-HUS patients患者已显示出积极的临床改善，并在某些情况下被证明是有效的 with[ Eculizumab191 has, shown337 positive, clinical338 improvement and proven effective in some cases [50][58][59].]。
2.3. Further Alternative Therapeutic Concepts其他替代治疗概念
Among在其他替代治疗策略中，一种有前途的方法是使用对各种血清型的 further alternative therapeutic strategies, a promising approach is the use of probiotic microorganisms showing antagonistic effects on EHEC strains ofEHEC 菌株表现出拮抗作用的益生菌微生物 [ various292 serotypes, [8][60][61][62].339 Suitable, vaccine340 candidates, against341 EHEC infections are polysaccharide conjugates such as constructs built up from ]。针对 EHE.C coli感染的合适候选疫苗是多糖结合物，例如由与细菌载体蛋白连接的大肠杆菌 O157 or或 E. coli 大肠杆菌O145 polysaccharides多糖构建的构建 体，为未来的临床研究提供有效预防性治疗的高前景 linked[ to342 bacterial, carrier343 proteins offering high prospects for effective preventive treatment for future clinical studies [63][64]. Phage therapy using specific phages against]。使用针对大肠杆菌的特定噬菌体进行噬菌体疗法 E. coli O157:H7 has也必须考虑在内。迄今为止，已知有 to be taken into consideration as well. More than 60 specific phages are known so far and in vitro experiments have been successful in elimination or reduction of60 多种特定噬菌体，体外实验已成功消除或减少 E. coli大肠杆菌 O157:H7 numbers,的数量，但体内实验的前景并不乐观 but[ in344 vivo experiments have not been as promising [65]. The proof or principle of the novel antibiotic]。据报道，新型抗生素-peptide肽 wrwycr has been reported effective in killing of EHEC in synergistic combination with antibiotic treatment without enhancing release of Stxs. This strategy offers a potential new candidate for a preventive antimicrobial for EHEC infections的证据或原理在与抗生素治疗协同组合时有效杀死 EHEC，而不会增强 Stxs 的释放。该策略为 EHEC 感染的预防性抗菌药物提供了潜在的新候选药物 [66][67].[ The345 retrograde, transport346]。内化的 of internalized Stx directly直接从早期内体逆行转运到高尔基体是绕过晚期内体和溶酶体降解的重要步骤，然后在酶活性部分易位至胞质溶胶中的核糖体靶标之前继续到达内质网。167、301、309、347、348、349、350 ]。_ from_ early_ endosomes_ to_ the_ Golgi_ apparatus_ is_ an_ essential_ step to这使得关键的逆行运输路线成为毒素运输小分子抑制剂的理想攻击点，作为作用于内体/高尔基体界面的可能治疗剂 [ bypass351 degradation, in352]。最近的评论 [ 6 the late endosomes and lysosomes, which297 then continues to the endoplasmic reticulum before translocation of the enzymatically active moiety]总结了干扰细胞内运输并抑制 to the ribosomal target in the cytosol [19][28][68][69][70][71][72]. This renders the crucial retrograde transportation route an ideal attack point for small molecule inhibitors of toxin trafficking as possible therapeutics acting at the endosome/Golgi interface [73][74]. Substances that interfere with intracellular trafficking inhibiting the transport of Stx have been summed in recent reviews [13][15] and will not be discussed further at this point.x 运输的物质，此时将不再进一步讨论。
2.4. Current Situation现在的情况
A一项综合研究总结了预防 comprehensive study that summarized the results of clinical trials for preventing EHEC-associated HUS including antibiotics, the Stx inhibitorEHEC 相关 HUS 的临床试验结果，包括抗生素、Stx 抑制剂 Synsorb Pk, and a monoclonal antibody against Stx ( 和针对 Stx 的单克隆抗体（Urtoxazumab) revealed），由于纳入的数量很少，因此没有关于这些干预措施有效性的确切结论。研究及其小样本量 [ no298 firm]。总的来说，尽管在理解 Stx 的分子机制方面取得了重大进展，这对于设计适当的药物或辅助治疗是必不可少的，但一种针对Stx的合理设计的药物尚未上市[ conclusions about the efficacy of these interventions given the small number of included studies and their small sample sizes [14]. Collectively, despite significant advances in understanding the molecular mechanisms of Stx being imperative for the design of appropriate drugs or adjunctive therapeutics, a rationally designed drug that targets Stx has yet not reached the market [13][14][50].191、297、298 ]。
