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dc.contributor.authorPoole, Jessica
dc.contributor.authorDay, Christopher J
dc.contributor.authorHaselhorst, Thomas
dc.contributor.authorJen, Freda E-C
dc.contributor.authorTorres, Victor J
dc.contributor.authorEdwards, Jennifer L
dc.contributor.authorJennings, Michael P
dc.date.accessioned2020-07-16T03:41:51Z
dc.date.available2020-07-16T03:41:51Z
dc.date.issued2020
dc.identifier.issn2150-7511
dc.identifier.doi10.1128/mBio.03046-19
dc.identifier.urihttp://hdl.handle.net/10072/395506
dc.description.abstractIn the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction. IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.relation.ispartofpagefrome03046-19:1
dc.relation.ispartofpagetoe03046-19:13
dc.relation.ispartofissue2
dc.relation.ispartofjournalmBio
dc.relation.ispartofvolume11
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchcode0605
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsCD11b I-domain
dc.subject.keywordsCR3
dc.titleRepurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationPoole, J; Day, CJ; Haselhorst, T; Jen, FE-C; Torres, VJ; Edwards, JL; Jennings, MP, Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells, mBio, 2020, 11 (2), pp. e03046-19:1-e03046-19:13
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2020-07-16T03:37:32Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2020 Poole et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorJen, Freda E.
gro.griffith.authorJennings, Michael P.
gro.griffith.authorHaselhorst, Thomas E.
gro.griffith.authorDay, Christopher J.
gro.griffith.authorPoole, Jessica


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