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dc.contributor.authorVedantam, Gayatri
dc.contributor.authorKochanowsky, Joshua
dc.contributor.authorLindsey, Jason
dc.contributor.authorMallozzi, Michael
dc.contributor.authorRoxas, Jennifer Lising
dc.contributor.authorAdamson, Chelsea
dc.contributor.authorAnwar, Farhan
dc.contributor.authorClark, Andrew
dc.contributor.authorClaus-Walker, Rachel
dc.contributor.authorMansoor, Asad
dc.contributor.authorMcQuade, Rebecca
dc.contributor.authorMonasky, Ross Calvin
dc.contributor.authorRamamurthy, Shylaja
dc.contributor.authorRoxas, Bryan
dc.contributor.authorViswanathan, V. K.
dc.date.accessioned2018-12-19T18:31:03Z
dc.date.available2018-12-19T18:31:03Z
dc.date.issued2018-09-05
dc.identifier.citationVedantam G, Kochanowsky J, Lindsey J, Mallozzi M, Roxas JL, Adamson C, Anwar F, Clark A, Claus-Walker R, Mansoor A, McQuade R, Monasky R, Ramamurthy S, Roxas B and Viswanathan VK (2018) An Engineered Synthetic Biologic Protects Against Clostridium difficile Infection. Front. Microbiol. 9:2080. doi: 10.3389/fmicb.2018.02080en_US
dc.identifier.issn1664-302X
dc.identifier.doi10.3389/fmicb.2018.02080
dc.identifier.urihttp://hdl.handle.net/10150/631219
dc.description.abstractMorbidity and mortality attributed to Clostridium difficile infection (CDI) have increased over the past 20 years. Currently, antibiotics are the only US FDA-approved treatment for primary C. difficile infection, and these are, ironically, associated with disease relapse and the threat of burgeoning drug resistance. We previously showed that non-toxin virulence factors play key roles in CDI, and that colonization factors are critical for disease. Specifically, a C. difficile adhesin, Surface Layer Protein A (SlpA) is a major contributor to host cell attachment. In this work, we engineered Syn-LAB 2.0 and Syn-LAB 2.1, two synthetic biologic agents derived from lactic acid bacteria, to stably and constitutively express a host-cell binding fragment of the C. difficile adhesin SlpA on their cell-surface. Both agents harbor conditional suicide plasmids expressing a codonoptimized chimera of the lactic acid bacterium's cell-wall anchoring surface-protein domain, fused to the conserved, highly adherent, host-cell-binding domain of C. difficile SlpA. Both agents also incorporate engineered biocontrol, obviating the need for any antibiotic selection. Syn-LAB 2.0 and Syn-LAB 2.1 possess positive biophysical and in vivo properties compared with their parental antecedents in that they robustly and constitutively display the SlpA chimera on their cell surface, potentiate human intestinal epithelial barrier function in vitro, are safe, tolerable and palatable to Golden Syrian hamsters and neonatal piglets at high daily doses, and are detectable in animal feces within 24 h of dosing, confirming robust colonization. In combination, the engineered strains also delay (in fixed doses) or prevent (when continuously administered) death of infected hamsters upon challenge with high doses of virulent C. difficile. Finally, fixeddose Syn-LAB ameliorates diarrhea in a non-lethal model of neonatal piglet enteritis. Taken together, our findings suggest that the two synthetic biologics may be effectively employed as non-antibiotic interventions for CDI.en_US
dc.description.sponsorshipNational Institutes of Health [AI121590]; US Department of Veterans Affairs [1I01BX001183-01]; USDA CSREES Hatch Program [ARZT-570410-A-02-139]; Asset Development Award from Tech Launch Arizonaen_US
dc.language.isoenen_US
dc.publisherFRONTIERS MEDIA SAen_US
dc.relation.urlhttps://www.frontiersin.org/article/10.3389/fmicb.2018.02080/fullen_US
dc.rights© 2018 Vedantam, Kochanowsky, Lindsey, Mallozzi, Roxas, Adamson, Anwar, Clark, Claus-Walker, Mansoor, McQuade, Monasky, Ramamurthy, Roxas and Viswanathan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).en_US
dc.subjectClostridium difficileen_US
dc.subjectinfectious diarrheaen_US
dc.subjectsynthetic biologyen_US
dc.subjectsurface layer proteinen_US
dc.subjectLactobacillusen_US
dc.titleAn Engineered Synthetic Biologic Protects Against Clostridium difficile Infectionen_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Sch Anim & Comparat Biomed Scien_US
dc.contributor.departmentUniv Arizona, Dept Immunobiolen_US
dc.contributor.departmentUniv Arizona, Inst Collaborat Res Bio5en_US
dc.identifier.journalFRONTIERS IN MICROBIOLOGYen_US
dc.description.noteOpen access journal.en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleFrontiers in Microbiology
dc.source.volume9
refterms.dateFOA2018-12-19T18:31:04Z


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