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dc.contributor.authorTotsika, Makrina
dc.contributor.authorVagenas, Dimitrios
dc.contributor.authorPaxman, Jason J
dc.contributor.authorWang, Geqing
dc.contributor.authorDhouib, Rabeb
dc.contributor.authorSharma, Pooja
dc.contributor.authorMartin, Jennifer L
dc.contributor.authorScanlon, Martin J
dc.contributor.authorHeras, Begona
dc.date.accessioned2019-08-20T04:45:03Z
dc.date.available2019-08-20T04:45:03Z
dc.date.issued2018
dc.identifier.issn1523-0864
dc.identifier.doi10.1089/ars.2017.7104
dc.identifier.urihttp://hdl.handle.net/10072/383471
dc.description.abstractAims: DsbA catalyzes disulfide bond formation in secreted and outer membrane proteins in bacteria. In pathogens, DsbA is a major facilitator of virulence constituting a target for antivirulence antimicrobial development. However, many pathogens encode multiple and diverse DsbA enzymes for virulence factor folding during infection. The aim of this study was to determine whether our recently identified inhibitors of Escherichia coli K-12 DsbA can inhibit the diverse DsbA enzymes found in two important human pathogens and attenuate their virulence. Results: DsbA inhibitors from two chemical classes (phenylthiophene and phenoxyphenyl derivatives) inhibited the virulence of uropathogenic E. coli and Salmonella enterica serovar Typhimurium, encoding two and three diverse DsbA homologues, respectively. Inhibitors blocked the virulence of dsbA null mutants complemented with structurally diverse DsbL and SrgA, suggesting that they were not selective for prototypical DsbA. Structural characterization of DsbA-inhibitor complexes showed that compounds from each class bind in a similar region of the hydrophobic groove adjacent to the Cys30-Pro31-His32-Cys33 (CPHC) active site. Modeling of DsbL- and SrgA-inhibitor interactions showed that these accessory enzymes could accommodate the inhibitors in their different hydrophobic grooves, supporting our in vivo findings. Further, we identified highly conserved residues surrounding the active site for 20 diverse bacterial DsbA enzymes, which could be exploited in developing inhibitors with a broad spectrum of activity. Innovation and Conclusion: We have developed tools to analyze the specificity of DsbA inhibitors in bacterial pathogens encoding multiple DsbA enzymes. This work demonstrates that DsbA inhibitors can be developed to target diverse homologues found in bacteria.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherMary Ann Liebert, Inc.
dc.relation.ispartofpagefrom653
dc.relation.ispartofpageto666
dc.relation.ispartofissue7
dc.relation.ispartofjournalAntioxidants & Redox Signaling
dc.relation.ispartofvolume29
dc.subject.fieldofresearchBiochemistry and Cell Biology
dc.subject.fieldofresearchMedical Biochemistry and Metabolomics
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0601
dc.subject.fieldofresearchcode1101
dc.subject.fieldofresearchcode1115
dc.titleInhibition of Diverse DsbA Enzymes in Multi-DsbA Encoding Pathogens
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by/4.0
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© Makrina Totsika, et al., 2018; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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gro.griffith.authorMartin, Jennifer


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