{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:18:23Z","timestamp":1767676703838,"version":"build-2065373602"},"reference-count":80,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2016,1,18]],"date-time":"2016-01-18T00:00:00Z","timestamp":1453075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Clostridium difficile infections can induce mild to severe diarrhoea and the often associated characteristic pseudomembranous colitis. Two protein toxins, the large glucosyltransferases TcdA and TcdB, are the main pathogenicity factors that can induce all clinical symptoms in animal models. The classical molecular mode of action of these homologous toxins is the inhibition of Rho GTPases by mono-glucosylation. Rho-inhibition leads to breakdown of the actin cytoskeleton, induces stress-activated and pro-inflammatory signaling and eventually results in apoptosis of the affected cells. An increasing number of reports, however, have documented further qualities of TcdA and TcdB, including the production of reactive oxygen species (ROS) by target cells. This review summarizes observations dealing with the production of ROS induced by TcdA and TcdB, dissects pathways that contribute to this phenomenon and speculates about ROS in mediating pathogenesis. In conclusion, ROS have to be considered as a discrete, glucosyltransferase-independent quality of at least TcdB, triggered by different mechanisms.<\/jats:p>","DOI":"10.3390\/toxins8010025","type":"journal-article","created":{"date-parts":[[2016,1,18]],"date-time":"2016-01-18T10:58:33Z","timestamp":1453114713000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Reactive Oxygen Species as Additional Determinants for Cytotoxicity of Clostridium difficile Toxins A and B"],"prefix":"10.3390","volume":"8","author":[{"given":"Claudia","family":"Fr\u00e4drich","sequence":"first","affiliation":[{"name":"Postgraduate Course for Toxicology and Environmental Toxicology, Institute for Legal Medicine, University of Leipzig, Johannisallee 28, Leipzig 04103, Germany"}]},{"given":"Lara-Antonia","family":"Beer","sequence":"additional","affiliation":[{"name":"Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany"}]},{"given":"Ralf","family":"Gerhard","sequence":"additional","affiliation":[{"name":"Postgraduate Course for Toxicology and Environmental Toxicology, Institute for Legal Medicine, University of Leipzig, Johannisallee 28, Leipzig 04103, Germany"},{"name":"Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany"}]}],"member":"1968","published-online":{"date-parts":[[2016,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/nrmicro2164","article-title":"Clostridium difficile infection: New developments in epidemiology and pathogenesis","volume":"7","author":"Rupnik","year":"2009","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/375500a0","article-title":"Glucosylation of Rho proteins by Clostridium difficile toxin B","volume":"375","author":"Just","year":"1995","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13932","DOI":"10.1074\/jbc.270.23.13932","article-title":"The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins","volume":"270","author":"Just","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1021\/pr300973q","article-title":"Substrate specificity of clostridial glucosylating toxins and their function on colonocytes analyzed by proteomics techniques","volume":"12","author":"Zeiser","year":"2013","journal-title":"J. Proteome Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1128\/CMR.18.2.247-263.2005","article-title":"Clostridium difficile toxins: Mechanism of action and role in disease","volume":"18","author":"Voth","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Schwan, C., Stecher, B., Tzivelekidis, T., van Ham, M., Rohde, M., Hardt, W.D., Wehland, J., and Aktories, K. (2009). Clostridium difficile toxin cdt induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000626"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4161\/gmic.26854","article-title":"Clostridium difficile binary toxin CDT: Mechanism, epidemiology, and potential clinical importance","volume":"5","author":"Gerding","year":"2014","journal-title":"Gut Microbes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1056\/NEJMoa051590","article-title":"An epidemic, toxin gene-variant strain of Clostridium difficile","volume":"353","author":"McDonald","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1042\/bj3510095","article-title":"Specificity and mechanism of action of some commonly used protein kinase inhibitors","volume":"351","author":"Davies","year":"2000","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.chembiol.2014.12.010","article-title":"Small molecule inhibitors of Clostridium difficile toxin b-induced cellular damage","volume":"22","author":"Tam","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.micpath.2011.10.009","article-title":"Release of TcdA and TcdB from Clostridium difficile cdi 630 is not affected by functional inactivation of the tcdE gene","volume":"52","author":"Olling","year":"2012","journal-title":"Microb. Pathog."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Govind, R., and Dupuy, B. (2012). Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002727"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1128\/iai.53.3.573-581.1986","article-title":"Cell surface binding site for Clostridium difficile enterotoxin: Evidence for a glycoconjugate containing the sequence Gal alpha 1\u20133Gal beta 1\u20134GlcNAc","volume":"53","author":"Krivan","year":"1986","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1128\/iai.59.1.73-78.1991","article-title":"Toxin a of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y","volume":"59","author":"Tucker","year":"1991","journal-title":"Infect. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3945","DOI":"10.1016\/j.febslet.2015.11.017","article-title":"Binding and entry of Clostridium difficile toxin B is mediated by multiple domains","volume":"24","author":"Manse","year":"2015","journal-title":"FEBS Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/cr.2014.169","article-title":"Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B","volume":"25","author":"Yuan","year":"2015","journal-title":"Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7073","DOI":"10.1073\/pnas.1500791112","article-title":"Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity","volume":"112","author":"LaFrance","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1128\/IAI.00326-08","article-title":"Gp96 is a human colonocyte plasma membrane binding protein for Clostridium difficile toxin A","volume":"76","author":"Na","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1172\/JCI118835","article-title":"Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A","volume":"98","author":"Pothoulakis","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3389\/fcimb.2012.00028","article-title":"Toward a structural understanding of Clostridium difficile toxins A and B","volume":"2","author":"Pruitt","year":"2012","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1099\/jmm.0.057828-0","article-title":"Cellular uptake of Clostridium difficile TcdA and truncated TcdA lacking the receptor binding domain","volume":"62","author":"Gerhard","year":"2013","journal-title":"J. Med. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Papatheodorou, P., Zamboglou, C., Genisyuerek, S., Guttenberg, G., and Aktories, K. (2010). Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010673"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.tim.2008.01.011","article-title":"Structure and mode of action of clostridial glucosylating toxins: The ABCD model","volume":"16","author":"Jank","year":"2008","journal-title":"Trends Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1128\/IAI.68.5.2470-2474.2000","article-title":"pH-Induced conformational changes in Clostridium difficile toxin B","volume":"68","author":"Spyres","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10670","DOI":"10.1074\/jbc.M009445200","article-title":"Low pH-induced formation of ion channels by Clostridium difficile toxin B in target cells","volume":"276","author":"Barth","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10808","DOI":"10.1074\/jbc.M512720200","article-title":"Cholesterol-dependent pore formation of Clostridium difficile toxin A","volume":"281","author":"Giesemann","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25314","DOI":"10.1074\/jbc.M703062200","article-title":"Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on cysteine protease activity","volume":"282","author":"Egerer","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3868","DOI":"10.1128\/IAI.00195-07","article-title":"Clostridium difficile toxins A and B directly stimulate human mast cells","volume":"75","author":"Meyer","year":"2007","journal-title":"Infect. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1159\/000332946","article-title":"Clostridium difficile toxins: Mediators of inflammation","volume":"4","author":"Shen","year":"2012","journal-title":"J. Innate Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.biocel.2007.12.014","article-title":"Clostridium difficile toxins: More than mere inhibitors of Rho proteins","volume":"40","author":"Genth","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1128\/jcm.15.6.1157-1158.1982","article-title":"Differential effects of Clostridium difficile toxins on tissue-cultured cells","volume":"15","author":"Donta","year":"1982","journal-title":"J. Clin. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1172\/JCI119698","article-title":"Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells","volume":"100","author":"Weidmann","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1007\/s10495-007-0074-8","article-title":"Clostridium difficile toxin A-induced apoptosis is p53-independent but depends on glucosylation of Rho GTPases","volume":"12","author":"Nottrott","year":"2007","journal-title":"Apoptosis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1046\/j.1462-5822.2002.00201.x","article-title":"Clostridium difficile toxin B activates dual caspase-dependent and caspase-independent apoptosis in intoxicated cells","volume":"4","author":"Ramsey","year":"2002","journal-title":"Cell Microbiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1086\/344729","article-title":"Mechanism of Clostridium difficile toxin A-induced apoptosis in T84 cells","volume":"186","author":"Brito","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1128\/IAI.73.3.1625-1634.2005","article-title":"Monocytes are highly sensitive to Clostridium difficile toxin A-induced apoptotic and nonapoptotic cell death","volume":"73","author":"Solomon","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s00210-010-0595-5","article-title":"Difference in the biological effects of Clostridium difficile toxin B in proliferating and non-proliferating cells","volume":"383","author":"Lica","year":"2011","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_38","first-page":"5","article-title":"Oxygen-derived species: Their relation to human disease and environmental stress","volume":"102","author":"Halliwell","year":"1994","journal-title":"Environ. Health Perspect."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"C341","DOI":"10.1152\/ajpcell.2000.279.2.C341","article-title":"Peroxynitrite-induced apoptosis involves activation of multiple caspases in HL-60 cells","volume":"279","author":"Zhuang","year":"2000","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S498","DOI":"10.1097\/01.CCM.0000186787.64500.12","article-title":"Reactive oxygen species","volume":"33","author":"Bayir","year":"2005","journal-title":"Crit. Care Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1477-3163-5-14","article-title":"Reactive oxygen species: Role in the development of cancer and various chronic conditions","volume":"5","author":"Waris","year":"2006","journal-title":"J. Carcinog."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.jbspin.2007.02.002","article-title":"Reactive oxygen species and superoxide dismutases: Role in joint diseases","volume":"74","author":"Afonso","year":"2007","journal-title":"Jt. Bone Spine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"L1005","DOI":"10.1152\/ajplung.2000.279.6.L1005","article-title":"Reactive oxygen species in cell signaling","volume":"279","author":"Thannickal","year":"2000","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.freeradbiomed.2009.12.022","article-title":"Reactive oxygen species, cellular redox systems, and apoptosis","volume":"48","author":"Circu","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0031-6997(24)01404-2","article-title":"Pharmacology of the eosinophil","volume":"51","author":"Giembycz","year":"1999","journal-title":"Pharmacol. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/jlb.60.6.677","article-title":"Assembly of the phagocyte NADPH oxidase: Molecular interaction of oxidase proteins","volume":"60","author":"DeLeo","year":"1996","journal-title":"J. Leukoc. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.4049\/jimmunol.170.5.2670","article-title":"Divergence of mechanisms regulating respiratory burst in blood and sputum eosinophils and neutrophils from atopic subjects","volume":"170","author":"Lacy","year":"2003","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1182\/blood-2003-07-2624","article-title":"Rac2 is critical for neutrophil primary granule exocytosis","volume":"104","author":"Steward","year":"2004","journal-title":"Blood"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1161\/01.RES.0000204727.46710.5e","article-title":"Regulation of nadph oxidases: The role of rac proteins","volume":"98","author":"Hordijk","year":"2006","journal-title":"Circ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7115","DOI":"10.1128\/MCB.16.12.7115","article-title":"Rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation","volume":"16","author":"Sulciner","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1124\/pr.110.002980","article-title":"NADPH oxidase-mediated redox signaling: Roles in cellular stress response, stress tolerance, and tissue repair","volume":"63","author":"Jiang","year":"2011","journal-title":"Pharmacol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Chumbler, N.M., Farrow, M.A., Lapierre, L.A., Franklin, J.L., Haslam, D.B., Goldenring, J.R., and Lacy, D.B. (2012). Clostridium difficile toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism. PLoS Pathog., 8.","DOI":"10.1371\/annotation\/f9017013-88c8-44db-818b-08b9322f3814"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"18674","DOI":"10.1073\/pnas.1313658110","article-title":"Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell nadph oxidase complex","volume":"110","author":"Farrow","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1099\/mic.0.066712-0","article-title":"A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile","volume":"159","author":"Donald","year":"2013","journal-title":"Microbiology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1111\/cmi.12317","article-title":"Pyknotic cell death induced by Clostridium difficile TcdB: Chromatin condensation and nuclear blister are induced independently of the glucosyltransferase activity","volume":"16","author":"Wohlan","year":"2014","journal-title":"Cell Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1007\/s10495-009-0353-7","article-title":"Apoptosis-inducing factor plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells","volume":"14","author":"Son","year":"2009","journal-title":"Apoptosis"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.1074\/jbc.M200212200","article-title":"Distinct modes of cell death induced by different reactive oxygen species: Amino acyl chloramines mediate hypochlorous acid-induced apoptosis","volume":"277","author":"Englert","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_58","first-page":"1835","article-title":"Intracellular ATP levels determine cell death fate by apoptosis or necrosis","volume":"57","author":"Eguchi","year":"1997","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3721","DOI":"10.1073\/pnas.1400680111","article-title":"Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore","volume":"111","author":"Zhang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1053\/gast.2000.8526","article-title":"Clostridium difficile toxin a causes early damage to mitochondria in cultured cells","volume":"119","author":"He","year":"2000","journal-title":"Gastroenterology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21237","DOI":"10.1074\/jbc.M413842200","article-title":"Clostridium difficile toxin A regulates inducible cyclooxygenase-2 and prostaglandin E2 synthesis in colonocytes via reactive oxygen species and activation of p38 mapk","volume":"280","author":"Kim","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_62","first-page":"G485","article-title":"Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats","volume":"276","author":"Qiu","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.micpath.2004.12.002","article-title":"Comparison of wild type with recombinant Clostridium difficile toxin a","volume":"38","author":"Gerhard","year":"2005","journal-title":"Microb. Pathog."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1038\/nrmicro1004","article-title":"Antimicrobial reactive oxygen and nitrogen species: Concepts and controversies","volume":"2","author":"Fang","year":"2004","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1111\/cmi.12410","article-title":"Human neutrophils are activated by a peptide fragment of Clostridium difficile toxin B presumably via formyl peptide receptor","volume":"17","author":"Goy","year":"2015","journal-title":"Cell Microbiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1172\/JCI113514","article-title":"Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes","volume":"81","author":"Pothoulakis","year":"1988","journal-title":"J. Clin. Investig."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.imlet.2015.02.007","article-title":"Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B","volume":"164","author":"Sun","year":"2015","journal-title":"Immunol. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1093\/abbs\/gmu091","article-title":"Recombinant Clostridium difficile toxin B induces endoplasmic reticulum stress in mouse colonal carcinoma cells","volume":"46","author":"Sun","year":"2014","journal-title":"Acta Biochim. Biophys. Sin. (Shanghai)"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.tim.2015.10.009","article-title":"Small molecules take a big step against Clostridium difficile","volume":"23","author":"Beilhartz","year":"2015","journal-title":"Trends Microbiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4129","DOI":"10.1128\/JCM.01104-10","article-title":"Assessment of Clostridium difficile infections by quantitative detection of TcdB toxin by use of a real-time cell analysis system","volume":"48","author":"Ryder","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3204","DOI":"10.1128\/JCM.01334-15","article-title":"Development and validation of digital enzyme-linked immunosorbent assays for ultrasensitive detection and quantification of Clostridium difficile toxins in stool","volume":"53","author":"Song","year":"2015","journal-title":"J. Clin. Microbiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1099\/mic.0.071365-0","article-title":"Clostridium difficile glutamate dehydrogenase is a secreted enzyme that confers resistance to H2O2","volume":"160","author":"Girinathan","year":"2014","journal-title":"Microbiology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1006\/abbi.1993.1065","article-title":"Purification and characterization of Clostridium difficile glutamate dehydrogenase","volume":"300","author":"Anderson","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1128\/JCM.00129-10","article-title":"Evaluation of the C. Diff quik chek complete assay, a new glutamate dehydrogenase and a\/b toxin combination lateral flow assay for use in rapid, simple diagnosis of Clostridium difficile disease","volume":"48","author":"Sharp","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1128\/JCM.01074-10","article-title":"Glutamate dehydrogenase for laboratory diagnosis of Clostridium difficile infection","volume":"48","author":"Goldenberg","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1111\/j.1365-2958.2008.06192.x","article-title":"Perr acts as a switch for oxygen tolerance in the strict anaerobe clostridium acetobutylicum","volume":"68","author":"Hillmann","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.2174\/092986712799828283","article-title":"Reactive oxygen production induced by the gut microbiota: Pharmacotherapeutic implications","volume":"19","author":"Jones","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/nature09674","article-title":"Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta-defensin 1","volume":"469","author":"Schroeder","year":"2011","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.mimet.2007.05.021","article-title":"The clostron: A universal gene knock-out system for the genus clostridium","volume":"70","author":"Heap","year":"2007","journal-title":"J. Microbiol. Methods"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Ng, Y.K., Ehsaan, M., Philip, S., Collery, M.M., Janoir, C., Collignon, A., Cartman, S.T., and Minton, N.P. (2013). Expanding the repertoire of gene tools for precise manipulation of the Clostridium difficile genome: Allelic exchange using pyrE alleles. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056051"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/8\/1\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:17:50Z","timestamp":1760210270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/8\/1\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,18]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,1]]}},"alternative-id":["toxins8010025"],"URL":"https:\/\/doi.org\/10.3390\/toxins8010025","relation":{},"ISSN":["2072-6651"],"issn-type":[{"type":"electronic","value":"2072-6651"}],"subject":[],"published":{"date-parts":[[2016,1,18]]}}}