Therapeutic Options of EHEC Infections: Comparison
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肠出血Enterohemorrhagic 性大肠杆菌Escherichia coli (EHEC) 是产志贺毒素are the human pathogenic subset of Shiga toxin (Stx)-producing 大肠杆菌的人类致病亚群E. coli (STEC)。. EHEC 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are responsible for severe colon infections associated with life-threatening extraintestinal complications such as the hemolytic-uremic syndrome (HUS) 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。 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.

  • EHEC
  • glycolipids
  • lipid rafts
  • STEC

1. 是否使用抗生素这是个问题Application of Antibiotics or Not That’s the Question

由于担心通过增加The Stx 产生来触发 HUS [285、286、287]，在administration of antibiotics in EHEC 感染中使用抗生素一直存在争议，并且仍然存在争议。infections was and remains controversial because of concerns about triggering HUS by increasing Stx production [1][2][3]. Stxs 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are encoded by genes located on genomes of lambdoid prophages and certain antibiotics stimulate their induction leading to enhanced production of Stxs 的产生增加[4]. Although numerous studies have reported that antibiotics enhance the severity of disease symptoms and increase the risk [of 288progression ]。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to HUS 发展的风险，使用某些development, further corroborated by in vitro antibiotic studies using certain 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 [strains, others have reported that antibiotics 289do ,not 290,have 291any ,effect 292or ,can 293even ,reduce 294the ,rate 295of ,HUS 296development ]。目前的数据情况得出的结论是，感染in EHEC 菌株、抗生素类型及其应用时机似乎显着影响infections [5][6][7][8][9][10][11][12]. The current data situation leads to the conclusion that the infecting EHEC 感染患者中strain, the type of antibiotic, and the timing of its application appear to significantly affect the development of HUS 的发展 [in EHEC-infected 285patients ]。[1].

2. 非抗生素疗法的发展Development of Non-Antibiotic Therapeutics

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In recent 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 相关的 HUS-associated HUS [13][14]. The majority of possible non-antibiotic therapeutics has been [or is in the developmental 297stage ,aimed 298to ]。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neutralize Stx，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 [, to prevent 6toxin adhesion, 156to block receptor biosynthesis, 293and to interfere trafficking, processing, and 299activity of the toxin within ,the 300cell ,[9][15][16][17][18][19]. 301]。由于Since Stx 诱导易感细胞分泌炎性细胞因子和趋化因子，从而导致induces the secretion of inflammatory cytokines and chemokines from susceptible cells that contribute to the pathogenesis of HUS 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, 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 大肠杆菌相关E. coli-associated HUS [ 302 ]。[20].

2.1。鞘糖脂生物合成抑制剂和. Inhibitors of Glycosphingolipid Biosynthesis and Stx 中和糖缀合物-Neutralizing Glycoconjugates

神经酰胺是所有复杂的两亲性鞘糖脂Ceramide is the hydrophobic backbone of all complex amphipathic glycosphingolipids (GSL) 的疏水骨架。其初始糖基化形成葡糖神经酰胺s). Its initial glycosylation forming glucosylceramide (GlcCer) 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is the first committed and rate-limiting step in the biosynthesis of GSLs with GlcCer core leading to the various GSL-families including the globo-series 系列在内的各种[21]. A number of GSLceramide 系列 [analogs such 303as ]。许多神经酰胺类似物，例如经典的classical D-PDMP 和许多其他类似物，过去已被仔细研究为 and many others has been scrutinized in the past as potential inhibitors of GlcCer 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 [synthase mainly developed for the treatment of human lipid storage diseases named as substrate 304reduction ,therapy 305[22][23][24][25][26]. ,The 306capability ,of 307traditional ,and 308]。传统和新型novel GlcCer 合酶抑制剂降低synthase inhibitors to reduce the cellular level of the Stx 受体receptor Gb3Cer 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 in various cell types including human epithelial and endothelial cells [27][28] and to prevent [the 183cytotoxic ,action 309toward ]this 并通过这种方式阻止way Gb3Cer 截短靶细胞的细胞毒性作用已加速另外关注 Stx 受体r-truncated target cells has expedited an additional focus on the Stx receptor Gb3Cer 作为 Stx 介导的 HUS 的治疗靶点。新开发的 as therapeutic target in Stx-mediated HUS. An example of a newly developed GlcCer 合酶抑制剂的一个例子是神经酰胺类似物-synthase inhibitor is the ceramide analog Eliglustat [[26], also primarily developed as an alternative approach to the enzyme replacement therapy of patients 308suffering ]，它也主要开发为from GSL 贮积病患者的酶替代疗法的替代方法storage diseases [29], effectively protects human renal tubular epithelial cells from Stx-caused cellular damage due to reducing [the 310]，由于降低细胞cellular Gb3Cer 水平，有效保护人肾小管上皮细胞免受levels suggesting its potential as Stx 引起的细胞损伤，这表明其作为protector [30][31]. The prevention of Gb3Cer-synthesis and neutralization of Stx-mediated 保护剂的潜力 [cytotoxic action 311by ,the 312ceramide ]。神经酰胺类似物analog C-9 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, 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 EHEC-HUS 提供了进一步的选择[[32][33].
Aligned to the opposite site of an 255、313 ]。_
与脂质锚的两亲性amphipathic GSL from 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 [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 of both compounds 314against ,Stx 315[34][35]. ]。2-脱氧-D-葡萄糖被掺入 GSL 的碳水化合物部分并保护细胞免受deoxy-D-glucose becomes incorporated into the carbohydrate moiety of GSLs and protects cells against Stxs [[34], 314]，而while 2-fluoro-2-deoxy-D-glucose 抑制inhibits GlcCer 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 [35]. SFurtx 侵害方面更有效 [hermore, the clinically 315approved ]。此外，临床批准的葡萄糖衍生物glucose-derivative Miglustat 已被证明在人类内皮细胞和上皮细胞中有效降低 Stx 受体has been shown being effective in human endothelial and epithelial cells to decrease the level of Stx receptor Gb3Cer 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[suggesting its application as a feasible strategy to protect kidney tissues from Stx-mediated kidney injury [36]. Collectively, the enumerated ceramide analogs and glucose-derivatives suggest potential clinical 316applications ]。总的来说，列举的神经酰胺类似物和葡萄糖衍生物表明for Stx 引起的疾病的潜在临床应用。-caused diseases.
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Since protein toxins of enterotoxic bacteria have proven to be attractive targets for [drug 300development [18][37], 317numerous therapeutic ]，因此已经开发了许多基于聚糖受体glycoconjugates Gb3 的 Stx 特异性类似物的治疗性糖缀合物 [based on Stx-specific analogs of the glycan receptor Gb3 have 297been ,developed 318[13][38]. ]。Synsorb Pk [ 319[39], ]、Starfish [[40], 320 ]、Daisy [[41], 321 ]、SUPER TWIGS [322、323[42][43], polymeric ] 、聚合丙烯酰胺acrylamide-Gb3 偶联物conjugates [[44], 324 ]、Gb3（聚糖）封装的金纳米粒子 [(glycan) 325、326encapsulated ]、新糖脂加标糖泡[gold 327nanoparticles [45][46], 328]neoglycolipid-spiked glycovesicles [47][48] or engineered probiotics 或在其表面表达expressing Gb3 类似物的工程益生菌analogs on their surface [49] are examples of glycoconstructs, [developed 329for ]neutralization 是糖结构的例子，它们是为中和 Stxs 而开发的，正如最近一篇很好且强烈推荐的综述of Stxs as described more precisely in a nice and highly recommended recent review [13]. However, although [effective 297in ]vitro, 中更准确地描述的那样。然而，虽然在体外有效，但潜在的 Stx 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 [potential Stx-binding neutralizers have failed in vivo showing no benefit in clinical trials and none of them has received clinical 191approval ,to 292date ]。[8][50].

2.2. 单克隆抗体Monoclonal Antibodies

尽管在产生中和人源化（嵌合）或人单克隆抗Despite a tremendous increase of knowledge has been gained with regard to the generation of neutralizing humanized (chimeric) or human monoclonal Stx 抗体以对抗 Stx 介导的疾病anti-Stx antibodies to combat Stx-mediated diseases [[51][52][53], 330so ,far 331no ,monoclonal 332antibody ]against 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Stx1(a) or Stx2(a) 已获得临床批准has received clinical approval [13][54]. The broadly administered anti-C5 [monoclonal 297antibody ,Eculizumab 333during ]。在the 2011 年德国爆发outbreak of an O104:H4 EHEC 菌株期间，广泛使用的抗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]. This anti-C5 单克隆抗体 Eculizumab 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 [complement blocker has obviously made the difference between favorable or detrimental outcome 334[55][56]. ]。这种抗The C5 补体阻滞剂显然在有利或不利结果之间产生了差异 [334、335 ]。_administration of Eculizumab 在伴有神经系统受累的in EHEC 相关 HUS 中使用-associated HUS with neurological involvement indicated that early use of Eculizumab 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appeared to improve neurological outcome, whereas late treatment seemed to show less benefit suggesting advantage of prophylactic Eculizumab 治疗的优势therapy before development of neurological symptoms [57]. [Thus, 336treatment ]。因此，用依库珠单抗治疗of EHEC-HUS 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 [patients with Eculizumab has shown positive clinical improvement and 191proven ,effective 337in ,some 338cases ]。[50][58][59].

2.3. 其他替代治疗概念Further Alternative Therapeutic Concepts

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Among further alternative therapeutic strategies, a promising approach is the use of probiotic microorganisms showing antagonistic effects on EHEC strains of various serotypes [8][60][61][62]. Suitable vaccine candidates against EHEC 菌株表现出拮抗作用的益生菌微生物infections [are 292polysaccharide ,conjugates 339such ,as 340constructs ,built 341up ]。针对 from EHEC. 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coli O157 或or E. coli 大肠杆菌O145 polysaccharides linked to bacterial carrier proteins offering high prospects for effective preventive treatment for future 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clinical studies [63][64]. Phage [therapy 342using ,specific 343phages ]。使用针对大肠杆菌的特定噬菌体进行噬菌体疗法against E. coli O157:H7 has 也必须考虑在内。迄今为止，已知有 60 多种特定噬菌体，体外实验已成功消除或减少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 of 大肠杆菌E. coli O157:H7 的数量，但体内实验的前景并不乐观numbers, but in vivo experiments have not been as promising [65]. The proof or principle of [the 344novel ]。据报道，新型抗生素antibiotic-肽peptide wrwycr 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 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 感染的预防性抗菌药物提供了潜在的新候选药物infections [66][67]. The [retrograde 345transport ,of 346]。内化的internalized Stx 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 ]。_directly from early endosomes to the Golgi apparatus is an essential step to bypass degradation in the late endosomes and lysosomes, which then continues to the endoplasmic reticulum before translocation of the enzymatically active moiety 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 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endosome/Golgi interface [73][74]. Substances that interfere [with 351intracellular ,trafficking 352]。最近的评论 [ 6inhibiting ,the 297transport ]总结了干扰细胞内运输并抑制of Stx 运输的物质，此时将不再进一步讨论。have been summed in recent reviews [13][15] and will not be discussed further at this point.

2.4. Current 现在的情况Situation

一项综合研究总结了预防A comprehensive study that summarized the results of clinical trials for preventing EHEC 相关 HUS 的临床试验结果，包括抗生素、Stx 抑制剂-associated HUS including antibiotics, the Stx inhibitor Synsorb Pk 和针对 Stx 的单克隆抗体（, and a monoclonal antibody against Stx (Urtoxazumab），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) revealed no firm 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 298the ]。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[market 191、297、298 ]。[13][14][50].

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