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Toxin Inhibitors for the Treatment of Clostridium Difficile Infection

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Toxin Inhibitors for the Treatment of Clostridium Difficile Infection Research Collection Doctoral Thesis Toxin Inhibitors for the Treatment of Clostridium difficile Infection Author(s): Ivarsson, Mattias E. Publication Date: 2014 Permanent Link: https://doi.org/10.3929/ethz-a-010345630 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 22210 Toxin Inhibitors for the Treatment of Clostridium difficile Infection A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich) presented by Mattias Emanuel IVARSSON MSc in Biomedical Engineering, ETH Zurich born on 10.3.1987 citizen of Zurich, Switzerland accepted on the recommendation of Prof. Jean-Christophe Leroux, examiner Prof. Bastien Castagner, co-examiner Prof. Wolf-Dietrich Hardt, co-examiner 2014 Abstract Clostridium difficile is a bacterial pathogen causing life-threatening infections that are the leading cause of hospital-acquired diarrhea. Recommended treatments for C. difficile infection (CDI) are limited to three antibiotics, which have unsatisfactory cure rates and lead to unacceptably high recurrence. The aim of the doctoral work presented herein was to explore the development of two novel therapeutic approaches against CDI. A variety of innovative therapeutic and prophylactic options against CDI are currently already in clinical trials, ranging from intestinal microbiota regeneration therapies to vaccines. These are presented and discussed in Chapter 1 of this thesis. Protein toxins constitute the main virulence factors of several species of bacteria and have proven to be attractive targets for drug development. Lead candidates that target bacterial toxins range from small molecules to polymeric binders, and act at each of the multiple steps in the process of toxin- mediated pathogenicity. Despite recent and significant advances in the field, a rationally designed drug that targets toxins has yet to reach the market. Chapter 2 presents the state of the art in bacterial toxin- targeted drug development with a critical consideration of achieved breakthroughs and withstanding challenges. The discussion focuses on A–B-type protein toxins secreted by four species of bacteria, namely C. difficile (toxins A and B), Vibrio cholerae (cholera toxin), enterohemorrhagic Escherichia coli (Shiga toxin), and Bacillus anthracis (anthrax toxin), which are the causative agents of diseases for which treatments need to be improved. The virulence of C. difficile toxins A and B (TcdA and TcdB) is modulated by intracellular auto- proteolysis following allosteric activation of their protease domains by inositol hexakisphosphate (IP6). In Chapter 3, we explore the possibility of inactivating the toxins by triggering their auto-proteolysis in the gut lumen prior to cell uptake using gain-of-function small molecules. The high calcium concentrations typically found in the gut precipitate IP6, precluding it from pre-emptively inducing toxin auto-proteolysis if administered exogenously. We therefore designed IP6 analogs with reduced susceptibility to complexation by calcium, which maintained allosteric activity at physiological calcium concentrations. We found that oral administration of IP2S4, a tetra-sulfated IP6 analog, attenuated inflammation in a mouse model of CDI. The first step in the uptake mechanism of TcdA and TcdB is binding to the epithelial cell surface. In Chapter 4, we sought to develop a polymeric binder for TcdA that would inhibit the toxin’s receptor binding and cellular uptake, thereby preventing its cytotoxicity. The design was based on multivalently grafting a known ligand for TcdA, αGal(1-3)βGal(1-4)Glc, to poly(hydroxypropyl methacrylamide), a flexible, biocompatible and water-soluble polymer extensively used for biomedical applications. The polymers we synthesized did not inhibit TcdA cytopathy in cellular assays. We hypothesized that this was most likely because they failed to prevent binding of the toxin to the cell surface, as evidenced by erythrocyte hemagglutination assays. We attributed the lack of activity observed to the low binding I ABSTRACT affinity of the ligand (∼ 1 mM) and the concurrent failure of the polymer to generate positive binding cooperativity between the multivalently displayed ligand and the toxin. Attempts to identify novel high affinity peptide ligands for the receptor binding domain of TcdA through phage display were not fruitful. The findings presented in this thesis have helped us to gain a deeper understanding of the opportunities and pitfalls of exploiting C. difficile toxins as therapeutic targets for the treatment of CDI. Although we were not able to create a polymeric binder effective at inhibiting the activity of TcdA, we succeeded in designing a small molecule capable of reducing CDI-associated symptoms in a mouse model of the infection. The latter result warrants further evaluation of the proposed molecule scaffold as a therapeutic option for treating CDI. II Résumé Clostridium difficile est une bactérie pathogène causant des infections potentiellement mortelles qui sont la cause principale de diarrhée nosocomiale. Le traitement contre une infection à C. difficile (ICD) est limité à un choix de trois antibiotiques, ayant des taux de guérison insuffisants et conduisant à un taux de récidive de l’infection inacceptable. L'objectif de la recherche présentée dans cette thèse était de mettre au point deux nouvelles approches thérapeutiques contre l’ICD. A l’heure actuelle, un nombre d'options thérapeutiques et prophylactiques novatrices contre l’ICD sont evaluées en essais cliniques. Celles-ci vont des thérapies de régénération du microbiote intestinal aux vaccins et sont discutées dans le chapitre 1 de cette thèse. Les toxines protéiques sont les principaux facteurs de virulence de plusieurs espèces de bactéries et se sont révélées être des cibles intéressantes pour le développement de médicaments. Les agents ciblant ces toxines bactériennes existent sous diverses formes, allant de petites molécules aux liants polymères, et agissent à différentes étapes du processus de pathogénicité des toxines. Malgré de récents progrès dans ce domaine, aucun principe actif conçu de manière rationnelle n'a encore été commercialisé. Le chapitre 2 décrit le développement de médicaments ciblant les toxines bactériennes en examinant de façon critique les percées réussies et les défis à surmonter. La discussion porte sur les toxines de type A-B sécrétée par quatre espèces de bactéries, à savoir C. difficile (toxines A et B), Vibrio cholerae (la toxine du choléra), Escherichia coli entérohémorragique (Shiga-toxines), et Bacillus anthracis (toxines létales et œdémateuses), qui sont les agents responsables de maladies pour lesquelles les traitements restent à être améliorées. La virulence des toxines A et B de C. difficile (TcdA et TcdB) est modulée par la protéolyse intracellulaire faisant suite à l’auto-activation allostérique de leurs domaines de protéase par l'inositol hexakisphosphate (IP6). Dans le chapitre 3, nous explorons la possibilité d’utiliser des petites molécules pour provoquer l’auto-protéolyse des toxines dans la lumière du gros intestin afin de les inactiver avant qu’elles ne soient absorbées par l’épithélium. Les concentrations élevées de calcium habituellement présentes dans l'intestin font précipiter l’IP6, l'empêchant d'induire l’auto-protéolyse des toxines suite à une administration exogène. Nous avons donc conçu des analogues d’IP6 ayant une susceptibilité réduite à complexer le calcium tout en maintenant une activité allostérique à des concentrations de calcium physiologiques. De plus, nous avons démontré que l'administration orale d’un de ces analogues (IP2S4), atténuait l’inflammation du colon dans un modèle murin d’ICD. La première étape du mécanisme d'absorption de TcdA et TcdB est leur liaison à la surface de l’épithélium intestinal. Dans le chapitre 4, nous avons cherché à développer un liant polymère pour la TcdA qui empêcherait la toxine de s’attacher aux cellules, inhibant ainsi sa cytotoxicité. La conception de ce polymère a consisté à greffer un ligand de TcdA, αGal(1-3)ßGal(1-4)Glc à un polymère d‘hydroxypropyle méthacrylamide de manière multivalente. Ce polymère est flexible, biocompatible, III RÉSUMÉ soluble dans l'eau et largement utilisé dans des applications biomédicales. Malheureusement, les polymères ainsi synthétisés se sont avérés inefficaces pour attenuer la cytopathie de la TcdA dans des essais cellulaires. Nous émettons l'hypothèse que les polymères ne sont pas parvenus à empêcher la liaison de la toxine à la surface des cellules, comme en ont témoigné les tests d'hémagglutination d’érythrocytes. Nous avons attribué le manque d'activité observé à la faible affinité du ligand pour la toxine (∼ 1 mM) et l'échec simultané du polymère à engendrer une coopérativité de liaison positive entre le ligand et la toxine. Nos tentatives visant à identifier par expression phagique de nouveaux ligands peptidiques de plus haute affinité pour la TcdA n’ont pas été fructueux. Les résultats présentés dans cette thèse nous ont aidés à mieux comprendre les possibilités et les défis liés à l’utilisation de toxines de C. difficile en tant que cibles thérapeutiques pour le traitement de l'ICD. Bien que nous n’ayons pas été en mesure de créer un liant polymère efficace pour inhiber l'activité de la TcdA, nous avons réussi à concevoir une petite molécule capable de réduire les symptômes
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