Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells

ABSTRACT In 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 galacto...

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Autores principales:	Jessica Poole, Christopher J. Day, Thomas Haselhorst, Freda E.-C. Jen, Victor J. Torres, Jennifer L. Edwards, Michael P. Jennings
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	CD11b I-domain CR3 complement receptor 3 Mac-1 Neisseria gonorrhoeae adherence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1fed3e7d06824e47b917fbd3f86a0f24
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spelling	oai:doaj.org-article:1fed3e7d06824e47b917fbd3f86a0f242021-11-15T15:57:02ZRepurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells10.1128/mBio.03046-192150-7511https://doaj.org/article/1fed3e7d06824e47b917fbd3f86a0f242020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03046-19https://doaj.org/toc/2150-7511ABSTRACT In 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.Jessica PooleChristopher J. DayThomas HaselhorstFreda E.-C. JenVictor J. TorresJennifer L. EdwardsMichael P. JenningsAmerican Society for MicrobiologyarticleCD11b I-domainCR3complement receptor 3Mac-1Neisseria gonorrhoeaeadherenceMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD11b I-domain CR3 complement receptor 3 Mac-1 Neisseria gonorrhoeae adherence Microbiology QR1-502
spellingShingle	CD11b I-domain CR3 complement receptor 3 Mac-1 Neisseria gonorrhoeae adherence Microbiology QR1-502 Jessica Poole Christopher J. Day Thomas Haselhorst Freda E.-C. Jen Victor J. Torres Jennifer L. Edwards Michael P. Jennings Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
description	ABSTRACT In 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.
format	article
author	Jessica Poole Christopher J. Day Thomas Haselhorst Freda E.-C. Jen Victor J. Torres Jennifer L. Edwards Michael P. Jennings
author_facet	Jessica Poole Christopher J. Day Thomas Haselhorst Freda E.-C. Jen Victor J. Torres Jennifer L. Edwards Michael P. Jennings
author_sort	Jessica Poole
title	Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
title_short	Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
title_full	Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
title_fullStr	Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
title_full_unstemmed	Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells
title_sort	repurposed drugs that block the gonococcus-complement receptor 3 interaction can prevent and cure gonococcal infection of primary human cervical epithelial cells
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/1fed3e7d06824e47b917fbd3f86a0f24
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Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells

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