Therapeutic Options of EHEC Infections: History
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Contributor:
Johanna Detzner
,
Gottfried Pohlentz
,
Johannes Müthing

Enterohemorrhagic Escherichia coli (EHEC) are the human pathogenic subset of Shiga toxin (Stx)-producing E. coli (STEC). EHEC are responsible for severe colon infections associated with life-threatening extraintestinal complications such as the hemolytic-uremic syndrome (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.

  • EHEC
  • glycolipids
  • lipid rafts
  • STEC

1. Application of Antibiotics or Not That’s the Question

The administration of antibiotics in EHEC infections was and remains controversial because of concerns about triggering HUS by increasing Stx production [1][2][3]. Stxs are encoded by genes located on genomes of lambdoid prophages and certain antibiotics stimulate their induction leading to enhanced production of Stxs [4]. Although numerous studies have 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 reported that antibiotics do not have any effect or can even reduce the rate of HUS development in EHEC infections [5][6][7][8][9][10][11][12]. The current data situation leads to the conclusion that the infecting EHEC strain, the type of antibiotic, and the timing of its application appear to significantly affect the development of HUS in EHEC-infected patients [1].

2. Development of Non-Antibiotic Therapeutics

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-associated HUS [13][14]. The majority of possible non-antibiotic therapeutics has been or is in the developmental stage aimed to neutralize Stx, to prevent toxin adhesion, to block receptor biosynthesis, and to interfere trafficking, processing, and activity of the toxin within the cell [9][15][16][17][18][19]. Since 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 E. coli-associated HUS [20].

2.1. Inhibitors of Glycosphingolipid Biosynthesis and Stx-Neutralizing Glycoconjugates

Ceramide is the hydrophobic backbone of all complex amphipathic glycosphingolipids (GSLs). Its initial glycosylation forming glucosylceramide (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 globo-series [21]. A number of ceramide analogs such as classical D-PDMP and many others has been scrutinized in the past as potential inhibitors of GlcCer synthase mainly developed for the treatment of human lipid storage diseases named as substrate reduction therapy [22][23][24][25][26]. The capability of traditional and novel GlcCer synthase inhibitors to reduce the cellular level of the Stx receptor Gb3Cer in various cell types including human epithelial and endothelial cells [27][28] and to prevent the cytotoxic action toward this way Gb3Cer-truncated target cells has expedited an additional focus on the Stx receptor Gb3Cer as therapeutic target in Stx-mediated HUS. An example of a newly developed GlcCer-synthase inhibitor is the ceramide analog Eliglustat [26], also primarily developed as an alternative approach to the enzyme replacement therapy of patients suffering from GSL storage diseases [29], effectively protects human renal tubular epithelial cells from Stx-caused cellular damage due to reducing the cellular Gb3Cer levels suggesting its potential as Stx protector [30][31]. The prevention of Gb3Cer-synthesis and neutralization of Stx-mediated cytotoxic action by the ceramide analog 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 EHEC-HUS [32][33].
Aligned 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 of both compounds against Stx [34][35]. 2-deoxy-D-glucose becomes incorporated into the carbohydrate moiety of GSLs and protects cells against Stxs [34], while 2-fluoro-2-deoxy-D-glucose inhibits 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 [35]. Furthermore, the clinically approved glucose-derivative Miglustat has been shown being effective in human endothelial and epithelial cells to decrease the level of Stx receptor Gb3Cer 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 applications for Stx-caused diseases.
Since protein toxins of enterotoxic bacteria have proven to be attractive targets for drug development [18][37], numerous therapeutic glycoconjugates based on Stx-specific analogs of the glycan receptor Gb3 have been developed [13][38]. Synsorb Pk [39], Starfish [40], Daisy [41], SUPER TWIGS [42][43], polymeric acrylamide-Gb3 conjugates [44], Gb3 (glycan) encapsulated gold nanoparticles [45][46], neoglycolipid-spiked glycovesicles [47][48] or engineered probiotics expressing Gb3 analogs on their surface [49] are examples of glycoconstructs, developed for neutralization of Stxs as described more precisely in a nice and highly recommended recent review [13]. However, although effective in vitro, potential Stx-binding neutralizers have failed in vivo showing no benefit in clinical trials and none of them has received clinical approval to date [8][50].

2.2. Monoclonal Antibodies

Despite a tremendous increase of knowledge has been gained with regard to the generation of neutralizing humanized (chimeric) or human monoclonal anti-Stx antibodies to combat Stx-mediated diseases [51][52][53], so far no monoclonal antibody against Stx1(a) or Stx2(a) has received clinical approval [13][54]. The broadly administered anti-C5 monoclonal antibody Eculizumab during the 2011 outbreak of an 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]. This anti-C5 complement blocker has obviously made the difference between favorable or detrimental outcome [55][56]. The administration of Eculizumab in EHEC-associated HUS with neurological involvement indicated that early use of Eculizumab appeared to improve neurological outcome, whereas late treatment seemed to show less benefit suggesting advantage of prophylactic Eculizumab therapy before development of neurological symptoms [57]. Thus, treatment of EHEC-HUS patients with Eculizumab has shown positive clinical improvement and proven effective in some cases [50][58][59].

2.3. Further Alternative Therapeutic Concepts

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 infections are polysaccharide conjugates such as constructs built up from E. coli O157 or E. coli O145 polysaccharides linked to bacterial carrier proteins offering high prospects for effective preventive treatment for future clinical studies [63][64]. Phage therapy using specific phages against E. coli O157:H7 has 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 E. coli O157:H7 numbers, but in vivo experiments have not been as promising [65]. The proof or principle of the novel antibiotic-peptide 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 [66][67]. The retrograde transport of internalized Stx 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 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.

2.4. Current Situation

A comprehensive study that summarized the results of clinical trials for preventing EHEC-associated HUS including antibiotics, the Stx inhibitor Synsorb Pk, and a monoclonal antibody against Stx (Urtoxazumab) 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 the market [13][14][50].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23136884

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