1,564
Views
0
CrossRef citations to date
0
Altmetric
Review

New treatment approaches for Clostridioides difficile infections: alternatives to antibiotics and fecal microbiota transplantation

, , , , & ORCID Icon
Article: 2337312 | Received 29 Jan 2024, Accepted 27 Mar 2024, Published online: 09 Apr 2024

References

  • Smits WK, Lyras D, Lacy DB, Wilcox MH, Kuijper EJ. Clostridium difficile infection. Nat Rev Dis Primers. 2016;2(1):1–34. doi:10.1038/nrdp.2016.20.
  • Napolitano LM, Edmiston CE Jr. Clostridium difficile disease: diagnosis, pathogenesis, and treatment update. Surgery. 2017;162(2):325–348. doi:10.1016/j.surg.2017.01.018.
  • Bouza E. Consequences of Clostridium difficile infection: understanding the healthcare burden. Clin Microbiol Infect: Official Publ Eur Soc Clin Microbiol Infect Dis. 2012;18(Suppl 6):5–12. doi:10.1111/1469-0691.12064.
  • Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009;7(7):526–536. doi:10.1038/nrmicro2164.
  • Khanafer N, Vanhems P, Barbut F, Luxemburger C, Group CS. Factors associated with Clostridium difficile infection: a nested case-control study in a three year prospective cohort. Anaerobe. 2017;44:117–123. doi:10.1016/j.anaerobe.2017.03.003.
  • Kordus SL, Thomas AK, Lacy DB. Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics. Nat Rev Microbiol. 2022;20(5):285–298. doi:10.1038/s41579-021-00660-2.
  • Papatheodorou P, Minton NP, Aktories K, Barth H. An updated view on the cellular uptake and mode-of-action of clostridioides difficile toxins. Adv Exp Med Biol. 2024;1435:219–247.
  • Olling A, Goy S, Hoffmann F, Tatge H, Just I, Gerhard R, Chakravortty D. The repetitive oligopeptide sequences modulate cytopathic potency but are not crucial for cellular uptake of Clostridium difficile toxin a. PLoS ONE. 2011;6(3):e17623. doi:10.1371/journal.pone.0017623.
  • Schorch B, Song S, van Diemen FR, Bock HH, May P, Herz J, Brummelkamp TR, Papatheodorou P, Aktories K. LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. Proc Natl Acad Sci USA. 2014;111(17):6431–6436. doi:10.1073/pnas.1323790111.
  • Gerding DN, Johnson S, Rupnik M, Aktories K. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes. 2014;5(1):15–27. doi:10.4161/gmic.26854.
  • Schwan C, Kruppke AS, Nolke T, Schumacher L, Koch-Nolte F, Kudryashev M, Stahlberg H, Aktories K. Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. Proc Natl Acad Sci USA. 2014;111(6):2313–2318. doi:10.1073/pnas.1311589111.
  • Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M, Hardt WD, Wehland J, Aktories K. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog. 2009;5(10):e1000626. doi:10.1371/journal.ppat.1000626.
  • van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, Krutova M, Norén T, Allerberger F, Coia JE, et al. European society of clinical microbiology and infectious diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021;27 Suppl 2:S1–S21. doi:10.1016/j.cmi.2021.09.038.
  • Bishop EJ, Tiruvoipati R. Management of Clostridioides difficile infection in adults and challenges in clinical practice: review and comparison of current IDSA/SHEA, ESCMID and ASID guidelines. J Antimicrob Chemother. 2022;78(1):21–30. doi:10.1093/jac/dkac404.
  • Ianiro G, Maida M, Burisch J, Simonelli C, Hold G, Ventimiglia M, Gasbarrini A, Cammarota G. Efficacy of different faecal microbiota transplantation protocols for Clostridium difficile infection: A systematic review and meta-analysis. United European Gastroenterol J. 2018;6(8):1232–1244. doi:10.1177/2050640618780762.
  • Li Y, Zhang T, Sun J, Liu N. Fecal microbiota transplantation and health outcomes: An umbrella review of meta-analyses of randomized controlled trials. Front Cell Infect Microbiol. 2022;12:899845. doi:10.3389/fcimb.2022.899845.
  • Mehta SR, Yen EF. Microbiota-based Therapies Clostridioides difficile infection that is refractory to antibiotic therapy. Transl Res. 2021;230:197–207. doi:10.1016/j.trsl.2020.11.013.
  • Schnizlein MK, Young VB. Capturing the environment of the Clostridioides difficile infection cycle. Nat Rev Gastro Hepat. 2022;19(8):508–520. doi:10.1038/s41575-022-00610-0.
  • Reigadas E, van Prehn J, Falcone M, Fitzpatrick F, Vehreschild M, Kuijper EJ, Bouza E. How to: prophylactic interventions for prevention of Clostridioides difficile infection. Clin Microbiol Infect. 2021;27(12):1777–1783. doi:10.1016/j.cmi.2021.06.037.
  • Orenstein R, Dubberke ER, Khanna S, Lee CH, Yoho D, Johnson S, Hecht G, DuPont HL, Gerding DN, Blount KF. et al. Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial. BMC Infect Dis. 2022;22(1):245. doi:10.1186/s12879-022-07256-y.
  • Khanna S, Sims M, Louie TJ, Fischer M, LaPlante K, Allegretti J, Hasson BR, Fonte AT, McChalicher C, Ege DS. et al. SER-109: An oral investigational microbiome therapeutic for patients with recurrent Clostridioides difficile Infection (rCDI). Antibiotics. 2022;11(9):11. doi:10.3390/antibiotics11091234.
  • Feuerstadt P, Louie TJ, Lashner B, Wang EEL, Diao L, Bryant JA, Sims M, Kraft CS, Cohen SH, Berenson CS. et al. SER-109, an oral microbiome therapy for recurrent clostridioides difficile infection. N Engl J Med. 2022;386(3):220–229. doi:10.1056/NEJMoa2106516.
  • Kao D, Wong K, Franz R, Cochrane K, Sherriff K, Chui L, Lloyd C, Roach B, Bai AD, Petrof EO. et al. The effect of a microbial ecosystem therapeutic (MET-2) on recurrent Clostridioides difficile infection: a phase 1, open-label, single-group trial. Lancet Gastroenterol Hepatol. 2021;6(4):282–291. doi:10.1016/S2468-1253(21)00007-8.
  • Chiu CW, Tsai PJ, Lee CC, Ko WC, Hung YP. Application of microbiome management in therapy for Clostridioides difficile Infections: From fecal microbiota transplantation to probiotics to microbiota-preserving antimicrobial agents. Pathogens. 2021;10(6):10. doi:10.3390/pathogens10060649.
  • Goldenberg JZ, Yap C, Lytvyn L, Lo CK, Beardsley J, Mertz D, Johnston BC. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Systematic Rev. 2017;2017(12):CD006095. doi:10.1002/14651858.CD006095.pub4.
  • Hell M, Bernhofer C, Stalzer P, Kern JM, Claassen E. Probiotics in Clostridium difficile infection: reviewing the need for a multistrain probiotic. Benef Microbes. 2013;4(1):39–51. doi:10.3920/BM2012.0049.
  • Liu D, Zeng L, Yan Z, Jia J, Gao J, Wei Y. The mechanisms and safety of probiotics against toxigenic clostridium difficile. Expert Rev Anti Infect Ther. 2020;18(10):967–975. doi:10.1080/14787210.2020.1778464.
  • Ma Y, Yang JY, Peng X, Xiao KY, Xu Q, Wang C. Which probiotic has the best effect on preventing Clostridium difficile-associated diarrhea? A systematic review and network meta-analysis. J Dig Dis. 2020;21(2):69–80. doi:10.1111/1751-2980.12839.
  • Mills JP, Rao K, Young VB. Probiotics for prevention of Clostridium difficile infection. Curr Opin Gastroenterol. 2018;34(1):3–10. doi:10.1097/MOG.0000000000000410.
  • Valdes-Varela L, Gueimonde M, Ruas-Madiedo P. Probiotics for prevention and treatment of Clostridium difficile Infection. Adv Exp Med Biol. 2018;1050:161–176.
  • Plummer S, Weaver MA, Harris JC, Dee P, Hunter J. Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhoea. Int Microbiol. 2004;7:59–62.
  • Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, Stollman NH. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021;116(6):1124–1147. doi:10.14309/ajg.0000000000001278.
  • Wullt M, Hagslatt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial. Scand J Infect Dis. 2003;35(6–7):365–367. doi:10.1080/00365540310010985.
  • Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006;83(6):1256–1264. doi:10.1093/ajcn/83.6.1256.
  • Borriello SP, Barclay FE. Protection of hamsters against Clostridium difficile ileocaecitis by prior colonisation with non-pathogenic strains. J Med Microbiol. 1985;19(3):339–350. doi:10.1099/00222615-19-3-339.
  • Wilson KH, Sheagren JN. Antagonism of toxigenic Clostridium difficile by nontoxigenic C. difficile. J Infect Dis. 1983;147(4):733–736. doi:10.1093/infdis/147.4.733.
  • Sambol SP, Merrigan MM, Tang JK, Johnson S, Gerding DN. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis. 2002;186(12):1781–1789. doi:10.1086/345676.
  • Merrigan MM, Sambol SP, Johnson S, Gerding DN. New approach to the management of Clostridium difficile infection: colonisation with non-toxigenic C. difficile during daily ampicillin or ceftriaxone administration. Int J Antimicrob Agents. 2009;33(Suppl 1):S46–50. doi:10.1016/S0924-8579(09)70017-2.
  • Villano SA, Seiberling M, Tatarowicz W, Monnot-Chase E, Gerding DN. Evaluation of an oral suspension of VP20621, spores of nontoxigenic Clostridium difficile strain M3, in healthy subjects. Antimicrob Agents Chemother. 2012;56(10):5224–5229. doi:10.1128/AAC.00913-12.
  • Gerding DN, Meyer T, Lee C, Cohen SH, Murthy UK, Poirier A, Van Schooneveld TC, Pardi DS, Ramos A, Barron MA. et al. Administration of spores of Nontoxigenic Clostridium difficile strain M3 for Prevention of Recurrent C difficile Infection. JAMA. 2015;313(17):1719–1727. doi:10.1001/jama.2015.3725.
  • Sambol SP, Skinner AM, Serna-Perez F, Owen B, Gerding DN, Johnson S, Carroll KC. Effective colonization by Nontoxigenic Clostridioides difficile REA strain M3 (NTCD-M3) spores following treatment with Either Fidaxomicin or Vancomycin. Microbiol Spectr. 2023;11(2):e0051723. doi:10.1128/spectrum.00517-23.
  • Vedantam G, Kochanowsky J, Lindsey J, Mallozzi M, Roxas JL, Adamson C, Anwar F, Clark A, Claus-Walker R, Mansoor A. et al. An engineered synthetic biologic protects against Clostridium difficile Infection. Front Microbiol. 2018;9:2080. doi:10.3389/fmicb.2018.02080.
  • Sehgal K, Khanna S. Immune response against Clostridioides difficile and translation to therapy. Therap Adv Gastroenterol. 2021;14:17562848211014817. doi:10.1177/17562848211014817.
  • Unger M, Eichhoff AM, Schumacher L, Strysio M, Menzel S, Schwan C, Alzogaray V, Zylberman V, Seman M, Brandner J. et al. Selection of nanobodies that block the enzymatic and cytotoxic activities of the binary Clostridium difficile toxin CDT. Sci Rep. 2015;5(1):7850. doi:10.1038/srep07850.
  • Yang Z, Ramsey J, Hamza T, Zhang Y, Li S, Yfantis HG, Lee D, Hernandez LD, Seghezzi W, Furneisen JM. et al. Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab. Infect Immun. 2015;83(2):822–831. doi:10.1128/IAI.02897-14.
  • Korbmacher M, Fischer S, Landenberger M, Papatheodorou P, Aktories K, Barth H. Human alpha-Defensin-5 Efficiently Neutralizes Clostridioides difficile Toxins TcdA, TcdB, and CDT. Front Pharmacol. 2020;11:1204. doi:10.3389/fphar.2020.01204.
  • Dzunkova M, D’Auria G, Xu H, Huang J, Duan Y, Moya A, Kelly CP, Chen X. The monoclonal antitoxin antibodies (Actoxumab–Bezlotoxumab) treatment facilitates normalization of the gut microbiota of mice with Clostridium difficile Infection. Front Cell Infect Microbiol. 2016;6:119. doi:10.3389/fcimb.2016.00119.
  • Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang X, Murgolo N, Ermakov G, DiNunzio E. et al. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem. 2014;289(26):18008–18021. doi:10.1074/jbc.M114.560748.
  • Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, Yacyshyn B, Kao D, Eves K, Ellison MC. et al. Bezlotoxumab for prevention of recurrent Clostridium difficile Infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649–656. doi:10.1093/cid/ciy171.
  • Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C. et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017;376(4):305–317. doi:10.1056/NEJMoa1602615.
  • Hernandez LD, Kroh HK, Hsieh E, Yang X, Beaumont M, Sheth PR, DiNunzio E, Rutherford SA, Ohi MD, Ermakov G. et al. Epitopes and mechanism of action of the Clostridium difficile Toxin A-Neutralizing antibody Actoxumab. J Mol Biol. 2017;429(7):1030–1044. doi:10.1016/j.jmb.2017.02.010.
  • Kroh HK, Chandrasekaran R, Zhang Z, Rosenthal K, Woods R, Jin X, Nyborg AC, Rainey GJ, Warrener P, Melnyk RA. et al. A neutralizing antibody that blocks delivery of the enzymatic cargo of Clostridium difficile toxin TcdB into host cells. J Biol Chem. 2018;293(3):941–952. doi:10.1074/jbc.M117.813428.
  • Davies NL, Compson JE, Mackenzie B, O’Dowd VL, Oxbrow AK, Heads JT, Turner A, Sarkar K, Dugdale SL, Jairaj M. et al. A mixture of functionally oligoclonal humanized monoclonal antibodies that neutralize Clostridium difficile TcdA and TcdB with high levels of in vitro potency shows in vivo protection in a hamster infection model. Clin Vaccine Immunol. 2013;20(3):377–390. doi:10.1128/CVI.00625-12.
  • Qiu H, Cassan R, Johnstone D, Han X, Joyee AG, McQuoid M, Masi A, Merluza J, Hrehorak B, Reid R. et al. Novel Clostridium difficile Anti-Toxin (TcdA and TcdB) humanized monoclonal antibodies demonstrate in vitro neutralization across a broad spectrum of clinical strains and in vivo potency in a Hamster Spore Challenge Model. PLOS ONE. 2016;11(6):e0157970. doi:10.1371/journal.pone.0157970.
  • Yan W, Shin KS, Wang SJ, Xiang H, Divers T, McDonough S, Bowman J, Rowlands A, Akey B, Mohamed H. et al. Equine hyperimmune serum protects mice against Clostridium difficile spore challenge. J Vet Sci. 2014;15(2):249–258. doi:10.4142/jvs.2014.15.2.249.
  • Roberts AK, Harris HC, Smith M, Giles J, Polak O, Buckley AM, Clark E, Ewin D, Moura IB, Spitall W. et al. A Novel, Orally Delivered Antibody Therapy and Its Potential to Prevent Clostridioides difficile Infection in Pre-clinical Models. Front Microbiol. 2020;11:578903. doi:10.3389/fmicb.2020.578903.
  • van Dissel JT, de Groot N, Hensgens CM, Numan S, Kuijper EJ, Veldkamp P, van ’t Wout J. Bovine antibody-enriched whey to aid in the prevention of a relapse of Clostridium difficile-associated diarrhoea: preclinical and preliminary clinical data. J Med Microbiol. 2005;54(2):197–205. doi:10.1099/jmm.0.45773-0.
  • Numan SC, Veldkamp P, Kuijper EJ, van den Berg RJ, van Dissel JT. Clostridium difficile-associated diarrhoea: bovine anti-Clostridium difficile whey protein to help aid the prevention of relapses. Gut. 2007;56(6):888–889. doi:10.1136/gut.2006.119016.
  • Hutton ML, Cunningham BA, Mackin KE, Lyon SA, James ML, Rood JI, Lyras D. Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative. Sci Rep. 2017;7(1):3665. doi:10.1038/s41598-017-03982-5.
  • Heidebrecht HJ, Weiss WJ, Pulse M, Lange A, Gisch K, Kliem H, Mann S, Pfaffl MW, Kulozik U, von Eichel-Streiber C. et al. Treatment and prevention of recurrent clostridium difficile infection with functionalized bovine antibody-enriched whey in a Hamster Primary Infection Model. Toxins. 2019;11(2):11. doi:10.3390/toxins11020098.
  • Heidebrecht HJ, Lagkouvardos I, Reitmeier S, Hengst C, Kulozik U, Pfaffl MW. Alteration of intestinal microbiome of Clostridioides difficile-Infected Hamsters during the Treatment with Specific Cow Antibodies. Antibiotics. 2021;10(6):10. doi:10.3390/antibiotics10060724.
  • Hussack G, Arbabi-Ghahroudi M, van Faassen H, Songer JG, Ng KK, MacKenzie R, Tanha J. Neutralization of Clostridium difficile toxin a with single-domain antibodies targeting the cell receptor binding domain. J Biol Chem. 2011;286(11):8961–8976. doi:10.1074/jbc.M110.198754.
  • Hussack G, Ryan S, van Faassen H, Rossotti M, MacKenzie CR, Tanha J, Chang Y-F. Neutralization of Clostridium difficile toxin B with VHH-Fc fusions targeting the delivery and CROPs domains. PLOS ONE. 2018;13(12):e0208978. doi:10.1371/journal.pone.0208978.
  • Andersen KK, Strokappe NM, Hultberg A, Truusalu K, Smidt I, Mikelsaar RH, Mikelsaar M, Verrips T, Hammarström L, Marcotte H. et al. Neutralization of Clostridium difficile Toxin B mediated by engineered Lactobacilli that produce single-domain antibodies. Infect Immun. 2016;84(2):395–406. doi:10.1128/IAI.00870-15.
  • Chen K, Zhu Y, Zhang Y, Hamza T, Yu H, Saint Fleur A, Galen J, Yang Z, Feng H. A probiotic yeast-based immunotherapy against Clostridioides difficile infection. Sci Transl Med. 2020;12(567):12. doi:10.1126/scitranslmed.aax4905.
  • Schmidt DJ, Beamer G, Tremblay JM, Steele JA, Kim HB, Wang Y, Debatis M, Sun X, Kashentseva EA, Dmitriev IP. et al. A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection. Clin Vaccine Immunol. 2016;23(9):774–784. doi:10.1128/CVI.00730-15.
  • Yang Z, Shi L, Yu H, Zhang Y, Chen K, Saint Fleur A, Bai G, Feng H. Intravenous adenovirus expressing a multi-specific, single-domain antibody neutralizing TcdA and TcdB protects mice from Clostridium difficile infection. Pathog Dis. 2016;74(7):ftw078. doi:10.1093/femspd/ftw078.
  • Simeon R, Jiang M, Chamoun-Emanuelli AM, Yu H, Zhang Y, Meng R, Peng Z, Jakana J, Zhang J, Feng H. et al. Selection and characterization of ultrahigh potency designed ankyrin repeat protein inhibitors of C. difficile toxin B. PLOS Biol. 2019;17(6):e3000311. doi:10.1371/journal.pbio.3000311.
  • Peng Z, Simeon R, Mitchell SB, Zhang J, Feng H, Chen Z, Limbago BM. Designed Ankyrin Repeat Protein (DARPin) Neutralizers of TcdB from Clostridium difficile Ribotype 027. mSphere. 2019;4(5):4. doi:10.1128/mSphere.00596-19.
  • Simeon RA, Zeng Y, Chonira V, Aguirre AM, Lasagna M, Baloh M, Sorg JA, Tommos C, Chen Z. Protease-stable DARPins as promising oral therapeutics. Protein Eng Des Sel. 2021;34. doi:10.1093/protein/gzab028.
  • Chen P, Zeng J, Liu Z, Thaker H, Wang S, Tian S, Zhang J, Tao L, Gutierrez CB, Xing L. et al. Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection. Nat Commun. 2021;12(1):3748. doi:10.1038/s41467-021-23878-3.
  • Babcock GJ, Broering TJ, Hernandez HJ, Mandell RB, Donahue K, Boatright N, Stack AM, Lowy I, Graziano R, Molrine D. et al. Human monoclonal antibodies directed against toxins a and B prevent Clostridium difficile-induced mortality in hamsters. Infect Immun. 2006;74(11):6339–6347. doi:10.1128/IAI.00982-06.
  • Zhang Z, Chen X, Hernandez LD, Lipari P, Flattery A, Chen SC, Kramer S, Polishook JD, Racine F, Cape H. et al. Toxin-mediated paracellular transport of antitoxin antibodies facilitates protection against Clostridium difficile infection. Infect Immun. 2015;83(1):405–416. doi:10.1128/IAI.02550-14.
  • Hernandez LD, Racine F, Xiao L, DiNunzio E, Hairston N, Sheth PR, Murgolo NJ, Therien AG. Broad coverage of genetically diverse strains of Clostridium difficile by actoxumab and bezlotoxumab predicted by in vitro neutralization and epitope modeling. Antimicrob Agents Chemother. 2015;59(2):1052–1060. doi:10.1128/AAC.04433-14.
  • Mohamed MFH, Ward C, Beran A, Abdallah MA, Asemota J, Kelly CR. Efficacy, Safety, and Cost-effectiveness of Bezlotoxumab in Preventing Recurrent Clostridioides difficile Infection: Systematic Review and Meta-analysis. J Clin Gastroenterol. 2023;58(4):389–401. doi:10.1097/MCG.0000000000001875.
  • Mileto SJ, Hutton ML, Walton SL, Das A, Ioannidis LJ, Ketagoda D, Quinn KM, Denton KM, Hansen DS, Lyras D. et al. Bezlotoxumab prevents extraintestinal organ damage induced by Clostridioides difficile infection. Gut Microbes. 2022;14(1):2117504. doi:10.1080/19490976.2022.2117504.
  • Goldsmith JA, Dewar V, Hermand P, Blais N, McLellan JS, Federle MJ. Structural Basis for Binding of Neutralizing Antibodies to Clostridioides difficile Binary Toxin. J Bacteriol. 2023;205(4):e0045622. doi:10.1128/jb.00456-22.
  • Cole LE, Li L, Jetley U, Zhang J, Pacheco K, Ma F, Zhang J, Mundle S, Yan Y, Barone L. et al. Deciphering the domain specificity of C. difficile toxin neutralizing antibodies. Vaccine. 2019;37(29):3892–3901. doi:10.1016/j.vaccine.2019.05.040.
  • Riley TV, Lyras D, Douce GR. Status of vaccine research and development for Clostridium difficile. Vaccine. 2019;37(50):7300–7306. doi:10.1016/j.vaccine.2019.02.052.
  • Kordus SL, Kroh HK, Rodriguez RC, Shrem RA, Peritore-Galve FC, Shupe JA, Wadzinski BE, Lacy DB, Spiller BW. Nanobodies against C. difficile TcdA and TcdB reveal unexpected neutralizing epitopes and provide a toolkit for toxin quantitation in vivo. PloS Pathog. 2023;19(10):e1011496. doi:10.1371/journal.ppat.1011496.
  • Hussack G, Rossotti MA, van Faassen H, Murase T, Eugenio L, Schrag JD, Ng KKS, Tanha J. Structure-guided design of a potent Clostridioides difficile toxin a inhibitor. Front Microbiol. 2023;14:1110541. doi:10.3389/fmicb.2023.1110541.
  • Yang Z, Schmidt D, Liu W, Li S, Shi L, Sheng J, Chen K, Yu H, Tremblay JM, Chen X. et al. A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice. J Infect Dis. 2014;210(6):964–972. doi:10.1093/infdis/jiu196.
  • Chen B, Perry K, Jin R. Neutralizing epitopes on Clostridioides difficile toxin a revealed by the structures of two camelid VHH antibodies. Front Immunol. 2022;13:978858. doi:10.3389/fimmu.2022.978858.
  • Guilleman MM, Stevens BAY, Van Lieshout LP, Rghei AD, Pei Y, Santry LA, Thompson B, Wootton SK. AAV-mediated delivery of actoxumab and bezlotoxumab results in serum and mucosal antibody concentrations that provide protection from C. difficile toxin challenge. Gene Ther. 2021;30(5):455–462. doi:10.1038/s41434-021-00236-y.
  • Skrlec K, Strukelj B, Berlec A. Non-immunoglobulin scaffolds: a focus on their targets. Trends Biotechnol. 2015;33(7):408–418. doi:10.1016/j.tibtech.2015.03.012.
  • Pluckthun A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu Rev Pharmacol Toxicol. 2015;55(1):489–511. doi:10.1146/annurev-pharmtox-010611-134654.
  • Adamson H, Ajayi MO, Gilroy KE, McPherson MJ, Tomlinson DC, Jeuken LJC. Rapid Quantification of C. difficile Glutamate Dehydrogenase and Toxin B (TcdB) with a NanoBiT Split-Luciferase Assay. Anal Chem. 2022;94(23):8156–8163. doi:10.1021/acs.analchem.1c05206.
  • Arthithanyaroj S, Chankhamhaengdecha S, Chaisri U, Aunpad R, Aroonnual A, Bhattacharjya S. Effective inhibition of Clostridioides difficile by the novel peptide CM-A. PLOS ONE. 2021;16(9):e0257431. doi:10.1371/journal.pone.0257431.
  • Fischer S, Uckert AK, Landenberger M, Papatheodorou P, Hoffmann-Richter C, Mittler AK, Ziener U, Hägele M, Schwan C, Müller M. et al. Human peptide α-defensin-1 interferes with Clostridioides difficile toxins TcdA, TcdB, and CDT. FASEB J. 2020;34(5):6244–6261. doi:10.1096/fj.201902816R.
  • Hong J, Zhang P, Yoon IN, Hwang JS, Kang JK, Kim H. The American Cockroach Peptide Periplanetasin-2 Blocks Clostridium Difficile Toxin A-Induced Cell Damage and Inflammation in the Gut. J Microbiol Biotechnol. 2017;27(4):694–700. doi:10.4014/jmb.1612.12012.
  • Yoon IN, Lu LF, Hong J, Zhang P, Kim DH, Kang JK, Hwang JS, Kim H. The American cockroach peptide periplanetasin-4 inhibits Clostridium difficile toxin A-induced cell toxicities and inflammatory responses in the mouse gut. J Pept Sci. 2017;23(11):833–839. doi:10.1002/psc.3046.
  • Hing TC, Ho S, Shih DQ, Ichikawa R, Cheng M, Chen J, Chen X, Law I, Najarian R, Kelly CP. et al. The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Gut. 2013;62(9):1295–1305. doi:10.1136/gutjnl-2012-302180.
  • Giesemann T, Guttenberg G, Aktories K. Human α-Defensins Inhibit Clostridium difficile Toxin B. Gastroenterology. 2008;134(7):2049–2058. doi:10.1053/j.gastro.2008.03.008.
  • Kudryashova E, Lu W, Kudryashov DS. Defensins versus pathogens: an unfolding story. Oncotarget. 2015;6(30):28533–28534. doi:10.18632/oncotarget.5109.
  • Kudryashova E, Quintyn R, Seveau S, Lu W, Wysocki VH, Kudryashov DS. Human defensins facilitate local unfolding of thermodynamically unstable regions of bacterial protein toxins. Immunity. 2014;41(5):709–721. doi:10.1016/j.immuni.2014.10.018.
  • Sarker P, Mily A, Mamun AA, Jalal S, Bergman P, Raqib R, Gudmundsson G, Agerberth B. Ciprofloxacin Affects Host Cells by Suppressing Expression of the Endogenous Antimicrobial Peptides Cathelicidins and Beta-Defensin-3 in Colon Epithelia. Antibiotics. 2014;3(3):353–374. doi:10.3390/antibiotics3030353.
  • de Gunzburg J, Ducher A, Modess C, Wegner D, Oswald S, Dressman J, Augustin V, Feger C, Andremont A, Weitschies W. et al. Targeted adsorption of molecules in the colon with the novel adsorbent-based medicinal product, DAV132: A proof of concept study in healthy subjects. J Clin Pharmacol. 2015;55(1):10–16. doi:10.1002/jcph.359.
  • Vehreschild M, Ducher A, Louie T, Cornely OA, Feger C, Dane A, Varastet M, Vitry F, de Gunzburg J, Andremont A. et al. An open randomized multicentre Phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones. J Antimicrob Chemother. 2022;77(4):1155–1165. doi:10.1093/jac/dkab474.
  • Vehreschild M, van Werkhoven CH, Biehl L, Dane A, de Kraker MEA, Mentré F, Burdet C, Glupczynski G, Timbermont L, Pfender E. et al. A Phase 3 Randomized Controlled Trial (MICROCARE) to Evaluate the Efficacy of DAV132 in Preventing Clostridioides Difficile Infection in Patients with Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome and Treated with Intensive Chemotherapy. Blood. 2021;138:4437.
  • Kokai-Kun JF, Roberts T, Coughlin O, Le CX, Whalen H, Stevenson R, Wacher VJ, Sliman J. Use of ribaxamase (SYN-004), a β-lactamase, to prevent Clostridium difficile infection in β-lactam-treated patients: a double-blind, phase 2b, randomised placebo-controlled trial. Lancet Infect Dis. 2019;19(5):487–496. doi:10.1016/S1473-3099(18)30731-X.
  • Kokai-Kun JF, Le C, Trout K, Cope JL, Ajami NJ, Degar AJ, Connelly S. Ribaxamase, an Orally Administered β-Lactamase, Diminishes Changes to Acquired Antimicrobial Resistance of the Gut Resistome in Patients Treated with Ceftriaxone. Infect Drug Resist. 2020;13:2521–2535. doi:10.2147/IDR.S260258.
  • Cubillos-Ruiz A, Alcantar MA, Donghia NM, Cardenas P, Avila-Pacheco J, Collins JJ. An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis. Nat Biomed Eng. 2022;6(7):910–921. doi:10.1038/s41551-022-00871-9.
  • Kortright KE, Chan BK, Koff JL, Turner PE. Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria. Cell Host Microbe. 2019;25(2):219–232. doi:10.1016/j.chom.2019.01.014.
  • Sangster W, Hegarty JP, Stewart DB. Phage therapy for Clostridium difficile infection: An alternative to antibiotics? Semin Colon Rectal Surg. 2014;25(3):167–170. doi:10.1053/j.scrs.2014.05.014.
  • Ramesh V, Fralick JA, Rolfe RD. Prevention of Clostridium difficile-induced ileocecitis with bacteriophage. Anaerobe. 1999;5(2):69–78. doi:10.1006/anae.1999.0192.
  • Sekulovic O, Garneau JR, Neron A, Fortier LC, Griffiths MW. Characterization of temperate phages infecting Clostridium difficile isolates of human and animal origins. Appl Environ Microb. 2014;80(8):2555–2563. doi:10.1128/AEM.00237-14.
  • Meader E, Mayer MJ, Steverding D, Carding SR, Narbad A. Evaluation of bacteriophage therapy to control Clostridium difficile and toxin production in an in vitro human colon model system. Anaerobe. 2013;22:25–30. doi:10.1016/j.anaerobe.2013.05.001.
  • Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepinski P, Douce GR, Clokie MRJ. Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth in vitro and Proliferation in vivo. Antimicrob Agents Chemother. 2016;60(2):968–981. doi:10.1128/AAC.01774-15.
  • Nale JY, Redgwell TA, Millard A, Clokie MRJ. Efficacy of an Optimised Bacteriophage Cocktail to Clear Clostridium difficile in a Batch Fermentation Model. Antibiotics. 2018;7(1):13. doi:10.3390/antibiotics7010013.
  • Whittle MJ, Bilverstone TW, van Esveld RJ, Lucke AC, Lister MM, Kuehne SA, Minton NP. A Novel Bacteriophage with Broad Host Range against Clostridioides difficile Ribotype 078 Supports SlpA as the Likely Phage Receptor. Microbiol Spectr. 2022;10(1):e0229521. doi:10.1128/spectrum.02295-21.
  • Selle K, Fletcher JR, Tuson H, Schmitt DS, McMillan L, Vridhambal GS, Rivera AJ, Montgomery SA, Fortier L-C, Barrangou R. et al. In vivo Targeting of Clostridioides difficile Using Phage-Delivered CRISPR-Cas3 Antimicrobials. mBio. 2020;11(2):11. doi:10.1128/mBio.00019-20.
  • Gebhart D, Williams SR, Bishop-Lilly KA, Govoni GR, Willner KM, Butani A, Sozhamannan S, Martin D, Fortier L-C, Scholl D. et al. Novel high-molecular-weight, R-type bacteriocins of Clostridium difficile. J Bacteriol. 2012;194(22):6240–6247. doi:10.1128/JB.01272-12.
  • Gebhart D, Lok S, Clare S, Tomas M, Stares M, Scholl D, Donskey CJ, Lawley TD, Govoni GR. et al. A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity. mBio. 2015;6(2):6. doi:10.1128/mBio.02368-14.
  • Wang Q, Euler CW, Delaune A, Fischetti VA. Using a Novel Lysin to Help Control Clostridium difficile Infections. Antimicrob Agents Chemother. 2015;59(12):7447–7457. doi:10.1128/AAC.01357-15.
  • Fujimoto K, Kimura Y, Shimohigoshi M, Satoh T, Sato S, Tremmel G, Uematsu M, Kawaguchi Y, Usui Y, Nakano Y. et al. Metagenome Data on Intestinal Phage-Bacteria Associations Aids the Development of Phage Therapy against Pathobionts. Cell Host & Microbe. 2020;28(3):380–389.e9. doi:10.1016/j.chom.2020.06.005.
  • Mayer MJ, Narbad A, Gasson MJ. Molecular characterization of a Clostridium difficile bacteriophage and its cloned biologically active endolysin. J Bacteriol. 2008;190(20):6734–6740. doi:10.1128/JB.00686-08.
  • Peng Z, Wang S, Gide M, Zhu D, Lamabadu Warnakulasuriya Patabendige HM, Li C, Cai J, Sun X. A Novel Bacteriophage Lysin-Human Defensin Fusion Protein Is Effective in Treatment of Clostridioides difficile Infection in Mice. Front Microbiol. 2018;9:3234. doi:10.3389/fmicb.2018.03234.
  • Meader E, Mayer MJ, Gasson MJ, Steverding D, Carding SR, Narbad A. Bacteriophage treatment significantly reduces viable Clostridium difficile and prevents toxin production in an in vitro model system. Anaerobe. 2010;16(6):549–554. doi:10.1016/j.anaerobe.2010.08.006.
  • Nale JY, Chutia M, Carr P, Hickenbotham PT, Clokie MR. ‘Get in Early’; Biofilm and Wax Moth (Galleria mellonella) Models Reveal New Insights into the Therapeutic Potential of Clostridium difficile Bacteriophages. Front Microbiol. 2016;7:1383. doi:10.3389/fmicb.2016.01383.
  • Jonczyk E, Klak M, Miedzybrodzki R, Gorski A. The influence of external factors on bacteriophages—review. Folia Microbiol (Praha). 2011;56(3):191–200. doi:10.1007/s12223-011-0039-8.
  • Unkmeir A, Schmidt H, O’Brien AD. Structural analysis of phage-borne stx genes and their flanking sequences in Shiga toxin-producing Escherichia coli and Shigella dysenteriae type 1 strains. Infect Immun. 2000;68(9):4856–4864. doi:10.1128/IAI.68.9.4856-4864.2000.
  • Goh S, Hussain H, Chang BJ, Emmett W, Riley TV, Mullany P, Onderdonk AB. Phage ϕC2 Mediates Transduction of Tn 6215 , Encoding Erythromycin Resistance, between Clostridium difficile Strains. mBio. 2013;4(6):e00840–13. doi:10.1128/mBio.00840-13.
  • Sekulovic O, Meessen-Pinard M, Fortier LC. Prophage-stimulated toxin production in Clostridium difficile NAP1/027 lysogens. J Bacteriol. 2011;193(11):2726–2734. doi:10.1128/JB.00787-10.
  • Revathi G, Fralick JA, Rolfe RD. In vivo lysogenization of a Clostridium difficile bacteriophage ФCD119. Anaerobe. 2011;17(3):125–129. doi:10.1016/j.anaerobe.2011.05.012.
  • Lenneman BR, Fernbach J, Loessner MJ, Lu TK, Kilcher S. Enhancing phage therapy through synthetic biology and genome engineering. Curr Opin Biotechnol. 2021;68:151–159. doi:10.1016/j.copbio.2020.11.003.
  • De Vos D, Verbeken G, Quintens J, Pirnay J-P. Phage Therapy in Europe: Regulatory and Intellectual Property Protection Issues. Phage Ther: A Practical Approach. 2019;363–377. Springer.
  • Ongenae V, Briegel A, Claessen D. Cell wall deficiency as an escape mechanism from phage infection. Open Biol. 2021;11(9):210199. doi:10.1098/rsob.210199.
  • Young R. Phage lysis: three steps, three choices, one outcome. J Microbiol. 2014;52(3):243–258. doi:10.1007/s12275-014-4087-z.
  • Mondal SI, Draper LA, Ross RP, Hill C. Bacteriophage endolysins as a potential weapon to combat Clostridioides difficile infection. Gut Microbes. 2020;12(1):1813533. doi:10.1080/19490976.2020.1813533.
  • Chandran C, Tham HY, Abdul Rahim R, Lim SHE, Yusoff K, Song AA. Lactococcus lactis secreting phage lysins as a potential antimicrobial against multi-drug resistant Staphylococcus aureus. PeerJ. 2022;10:e12648. doi:10.7717/peerj.12648.
  • Rahman MU, Wang W, Sun Q, Shah JA, Li C, Sun Y, Li Y, Zhang B, Chen W, Wang S. et al. Endolysin, a Promising Solution against Antimicrobial Resistance. Antibiotics. 2021;10(11):10. doi:10.3390/antibiotics10111277.
  • Low LY, Yang C, Perego M, Osterman A, Liddington R. Role of net charge on catalytic domain and influence of cell wall binding domain on bactericidal activity, specificity, and host range of phage lysins. J Biol Chem. 2011;286(39):34391–34403. doi:10.1074/jbc.M111.244160.
  • Phothichaisri W, Chankhamhaengdecha S, Janvilisri T, Nuadthaisong J, Phetruen T, Fagan RP, Chanarat S. Potential Role of the Host-Derived Cell-Wall Binding Domain of Endolysin CD16/50L as a Molecular Anchor in Preservation of Uninfected Clostridioides difficile for New Rounds of Phage Infection. Microbiol Spectr. 2022;10(2):e0236121. doi:10.1128/spectrum.02361-21.
  • McGowan S, Buckle AM, Mitchell MS, Hoopes JT, Gallagher DT, Heselpoth RD, Shen Y, Reboul CF, Law RHP, Fischetti VA. et al. X-ray crystal structure of the streptococcal specific phage lysin PlyC. Proc Natl Acad Sci USA. 2012;109(31):12752–12757. doi:10.1073/pnas.1208424109.
  • Mayer MJ, Garefalaki V, Spoerl R, Narbad A, Meijers R. Structure-based modification of a Clostridium difficile-targeting endolysin affects activity and host range. J Bacteriol. 2011;193(19):5477–5486. doi:10.1128/JB.00439-11.
  • Mehta KK, Paskaleva EE, Wu X, Grover N, Mundra RV, Chen K, Zhang Y, Yang Z, Feng H, Dordick JS. et al. Newly identified bacteriolytic enzymes that target a wide range of clinical isolates of Clostridium difficile. Biotechnol Bioeng. 2016;113(12):2568–2576. doi:10.1002/bit.26029.
  • Oechslin F. Resistance Development to Bacteriophages Occurring during Bacteriophage Therapy. Viruses. 2018;10(7):10. doi:10.3390/v10070351.
  • Martens EC, Neumann M, Desai MS. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nat Rev Microbiol. 2018;16(8):457–470. doi:10.1038/s41579-018-0036-x.
  • Xu B, Wu X, Gong Y, Cao J. IL-27 induces LL-37/CRAMP expression from intestinal epithelial cells: implications for immunotherapy of Clostridioides difficile infection. Gut Microbes. 2021;13(1):1968258. doi:10.1080/19490976.2021.1968258.
  • Sadighi Akha AA, McDermott AJ, Theriot CM, Carlson PE Jr., Frank CR, McDonald RA, Falkowski NR, Bergin IL, Young VB, Huffnagle GB. Interleukin-22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice. Immunology. 2015;144(4):587–597. doi:10.1111/imm.12414.
  • Frisbee AL, Saleh MM, Young MK, Leslie JL, Simpson ME, Abhyankar MM, Cowardin CA, Ma JZ, Pramoonjago P, Turner SD. et al. IL-33 drives group 2 innate lymphoid cell-mediated protection during Clostridium difficile infection. Nat Commun. 2019;10(1):2712. doi:10.1038/s41467-019-10733-9.
  • Wang J, Ortiz C, Fontenot L, Mukhopadhyay R, Xie Y, Chen X, Feng H, Pothoulakis C, Koon HW. Therapeutic Mechanism of Macrophage Inflammatory Protein 1 α Neutralizing Antibody (CCL3) in Clostridium difficile Infection in Mice. J Infect Dis. 2020;221(10):1623–1635. doi:10.1093/infdis/jiz640.
  • Buonomo EL, Madan R, Pramoonjago P, Li L, Okusa MD, Petri WA Jr. Role of interleukin 23 signaling in Clostridium difficile colitis. J Infect Dis. 2013;208(6):917–920. doi:10.1093/infdis/jit277.
  • Woods EC, Edwards AN, Childress KO, Jones JB, McBride SM, Shen A. The C. difficile clnRAB operon initiates adaptations to the host environment in response to LL-37. PLoS Pathog. 2018;14(8):e1007153. doi:10.1371/journal.ppat.1007153.
  • Rizvi A, Vargas-Cuebas G, Edwards AN, DiCandia MA, Carter ZA, Lee CD, Monteiro MP, McBride SM. Glycine fermentation by C. difficile promotes virulence and spore formation, and is induced by host cathelicidin. Infect Immun. 2023;91(10):e0031923. doi:10.1128/iai.00319-23.
  • Nagao-Kitamoto H, Leslie JL, Kitamoto S, Jin C, Thomsson KA, Gillilland MG 3rd, Kuffa P, Goto Y, Jenq RR, Ishii C. et al. Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota. Nat Med. 2020;26(4):608–617. doi:10.1038/s41591-020-0764-0.
  • Saleh MM, Petri WA Jr., Bäumler AJ. Type 3 Immunity during Clostridioides difficile Infection: Too Much of a Good Thing? Infect Immun. 2019;88(1):88. doi:10.1128/IAI.00306-19.
  • Saleh MM, Frisbee AL, Leslie JL, Buonomo EL, Cowardin CA, Ma JZ, Simpson ME, Scully KW, Abhyankar MM, Petri WA. Colitis-Induced Th17 Cells Increase the Risk for Severe Subsequent Clostridium difficile Infection. Cell Host & Microbe. 2019;25(5):756–765.e5. doi:10.1016/j.chom.2019.03.003.
  • Stroke IL, Letourneau JJ, Miller TE, Xu Y, Pechik I, Savoly DR, Ma L, Sturzenbecker LJ, Sabalski J, Stein PD. et al. Treatment of Clostridium difficile Infection with a Small-Molecule Inhibitor of Toxin UDP-Glucose Hydrolysis Activity. Antimicrob Agents Chemother. 2018;62(5):62. doi:10.1128/AAC.00107-18.
  • Bender KO, Garland M, Ferreyra JA, Hryckowian AJ, Child MA, Puri AW, Solow-Cordero DE, Higginbottom SK, Segal E, Banaei N. et al. A small-molecule antivirulence agent for treating Clostridium difficile infection. Sci Transl Med. 2015;7(306):306ra148. doi:10.1126/scitranslmed.aac9103.
  • Ivarsson ME, Durantie E, Huberli C, Huwiler S, Hegde C, Friedman J, Altamura F, Lu J, Verdu EF, Bercik P. et al. Small-Molecule Allosteric Triggers of Clostridium difficile Toxin B Auto-proteolysis as a Therapeutic Strategy. Cell Chem Biol. 2019;26(1):17–26.e13. doi:10.1016/j.chembiol.2018.10.002.
  • Tam J, Hamza T, Ma B, Chen K, Beilhartz GL, Ravel J, Feng H, Melnyk RA. Host-targeted niclosamide inhibits C. difficile virulence and prevents disease in mice without disrupting the gut microbiota. Nat Commun. 2018;9(1):5233. doi:10.1038/s41467-018-07705-w.
  • Julliard W, De Wolfe TJ, Fechner JH, Safdar N, Agni R, Mezrich JD. Amelioration of Clostridium difficile Infection in Mice by Dietary Supplementation with Indole-3-carbinol. Annals Of Surgery. 2017;265(6):1183–1191. doi:10.1097/SLA.0000000000001830.
  • Wang S, Deng W, Li F, Chen YE, Wang PU. Blockade of T helper 17 cell function ameliorates recurrent Clostridioides difficile infection in mice. Acta Biochim Biophys Sin (Shanghai). 2021;53(10):1290–1299. doi:10.1093/abbs/gmab107.
  • Andersson JA, Peniche AG, Galindo CL, Boonma P, Sha J, Luna RA, Savidge TC, Chopra AK, Dann SM. et al. New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection. mBio. 2020;11(2):11. doi:10.1128/mBio.00053-20.
  • Hansen A, Alston L, Tulk SE, Schenck LP, Grassie ME, Alhassan BF, Veermalla AT, Al-Bashir S, Gendron F-P, Altier C. et al. The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction. PLoS ONE. 2013;8(11):e81491. doi:10.1371/journal.pone.0081491.
  • Tam J, Icho S, Utama E, Orrell KE, Gomez-Biagi RF, Theriot CM, Kroh HK, Rutherford SA, Lacy DB, Melnyk RA. Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin. Proc Natl Acad Sci USA. 2020;117(12):6792–6800. doi:10.1073/pnas.1916965117.
  • Howerton A, Patra M, Abel-Santos E. A new strategy for the prevention of Clostridium difficile infection. J Infect Dis. 2013;207(10):1498–1504. doi:10.1093/infdis/jit068.
  • Howerton A, Seymour CO, Murugapiran SK, Liao Z, Phan JR, Estrada A, Wagner AJ, Mefferd CC, Hedlund BP, Abel-Santos E. et al. Effect of the Synthetic Bile Salt Analog CamSA on the Hamster Model of Clostridium difficile Infection. Antimicrob Agents Chemother. 2018;62(10):62. doi:10.1128/AAC.02251-17.
  • Jose S, Mukherjee A, Horrigan O, Setchell KDR, Zhang W, Moreno-Fernandez ME, Andersen H, Sharma D, Haslam DB, Divanovic S. et al. Obeticholic acid ameliorates severity of Clostridioides difficile infection in high fat diet-induced obese mice. Mucosal Immunol. 2021;14(2):500–510. doi:10.1038/s41385-020-00338-7.
  • Hutton ML, Pehlivanoglu H, Vidor CJ, James ML, Thomson MJ, Lyras D. Repurposing auranofin as a Clostridioides difficile therapeutic. J Antimicrob Chemother. 2020;75:409–417. doi:10.1093/jac/dkz430.
  • Abutaleb NS, Seleem MN. Auranofin, at clinically achievable dose, protects mice and prevents recurrence from Clostridioides difficile infection. Sci Rep. 2020;10(1):7701. doi:10.1038/s41598-020-64882-9.
  • Zackular JP, Kirk L, Trindade BC, Skaar EP, Aronoff DM. Misoprostol protects mice against severe Clostridium difficile infection and promotes recovery of the gut microbiota after antibiotic perturbation. Anaerobe. 2019;58:89–94. doi:10.1016/j.anaerobe.2019.06.006.
  • Blount KF, Megyola C, Plummer M, Osterman D, O’Connell T, Aristoff P, Quinn C, Chrusciel RA, Poel TJ, Schostarez HJ. et al. Novel riboswitch-binding flavin analog that protects mice against Clostridium difficile infection without inhibiting cecal flora. Antimicrob Agents Chemother. 2015;59(9):5736–5746. doi:10.1128/AAC.01282-15.
  • Schumacher J, Nienhaus A, Heber S, Matylitsky J, Chaves-Olarte E, Rodriguez C, Barth H, Papatheodorou P. Exploring the inhibitory potential of the antiarrhythmic drug amiodarone against Clostridioides difficile toxins TcdA and TcdB. Gut Microbes. 2023;15(2):2256695. doi:10.1080/19490976.2023.2256695.
  • Capone A, Volpe E. Transcriptional regulators of T Helper 17 cell differentiation in health and autoimmune diseases. Front Immunol. 2020;11:348. doi:10.3389/fimmu.2020.00348.
  • Wang S, Deng W, Li F, Xiang L, Lv P, Chen Y. Treatment with butyrate alleviates dextran sulfate sodium and Clostridium difficile-induced colitis by preventing activity of Th17 cells via regulation of SIRT1/mTOR in mice. J Nutr Biochem. 2023;111:109155. doi:10.1016/j.jnutbio.2022.109155.
  • Johnstone MA, Holman MA, Self WT. Inhibition of selenoprotein synthesis is not the mechanism by which auranofin inhibits growth of Clostridioides difficile. Sci Rep. 2023;13(1):14733. doi:10.1038/s41598-023-36796-9.
  • Delattre R, Seurat J, Haddad F, Nguyen TT, Gaborieau B, Kane R, Dufour N, Ricard J-D, Guedj J, Debarbieux L. et al. Combination of in vivo phage therapy data with in silico model highlights key parameters for pneumonia treatment efficacy. Cell Rep. 2022;39(7):110825. doi:10.1016/j.celrep.2022.110825.
  • Danis-Wlodarczyk KM, Wozniak DJ, Abedon ST. Treating bacterial infections with bacteriophage-based enzybiotics: In Vitro, in vivo and clinical application. Antibiotics. 2021;10(12):10. doi:10.3390/antibiotics10121497.
  • Oliveira H, Sao-Jose C, Azeredo J. Phage-derived peptidoglycan degrading enzymes: challenges and future prospects for in vivo Therapy. Viruses. 2018;10(6):10. doi:10.3390/v10060292.