To Örebro University

oru.seÖrebro University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Serum complement activation by C4BP-IgM fusion protein can restore susceptibility to antibiotics in Neisseria gonorrhoeae
Department of Translational Medicine, Lund University, Malmö, Sweden.
Department of Translational Medicine, Lund University, Malmö, Sweden.
Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD, Australia.
Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD, Australia.
Show others and affiliations
2022 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 141, p. 215-215Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: The sexually transmitted infection gonorrhea is a common health problem worldwide causing critical reproductive sequelae such as infertility. An effective vaccine remains elusive and antibiotics used in clinics are becoming ineffective because of the rapid spread of resistance among Neisseria gonorrhoeae, the causative organism of gonorrhea. We previously created a human fusion protein called C4BP-IgM to mark and eliminate bacteria by activating host complement. C4BP-IgM links the two N-terminal domains of C4BP, which bind to gonococci, with the Fc domain of IgM to increase complement activation on and kill bacteria. We documented that C4BP-IgM enhances bactericidal activity of serum against clinical C4BP-binding gonococcal isolates from patients, and markedly attenuated the duration and burden of gonococcal infection in a mouse vaginal colonizationmodel 1. Here, we explore the activity of C4BP-IgM as an adjuvant to several antibiotics (spectinomycin, azithromycin, cefixime, ceftriaxone and ciprofloxacin) currently or previously used to treat gonorrhea.

Materials and methods: Cooperative bactericidal activity between C4BP-IgM, complement and antibiotics was evaluated by monitoring survival and membrane alterations of a laboratory isolate and two clinical azithromycin-resistant gonococcal strains, which also resisted killing by normal human serum. Effect of complement and C4BP-IgM on uptake and intracellular activity of selected antibiotics was also assessed.

Results: We found that human serum, as source of complement components, reduced MIC values of antibiotics against N. gonorrhoeae. Addition of C4BP-IgM at concentrations which only partially reduced survival, induced complete killing of bacteria when both serum and antibiotics were present. Bactericidal cooperation between complement and antimicrobials was revealed to be triggered by membrane damage induced by C4BP-IgM complement activation. Formation of membrane attack complex pores on bacteria facilitated uptake of antimicrobials, which in turn enhanced their intracellular concentration and activity. Remarkably, C4BP-IgM restored susceptibility to azithromycin of two azithromycin-resistant clinical gonococcal strains that overexpressed the MtrC-MtrD-MtrE efflux pump.

Conclusion: We provide proof-of-principle for the use of C4BP-IgM fusion protein as an adjuvant to antibiotics, which could be re-purposed for clinical use pending the development of effective new treatments.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 141, p. 215-215
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:oru:diva-98827ISI: 000773913400204OAI: oai:DiVA.org:oru-98827DiVA, id: diva2:1655297
Conference
28th International Complement Workshop (ICW 2021), (Virtual workshop), December 7-10, 2022
Available from: 2022-05-02 Created: 2022-05-02 Last updated: 2022-05-02Bibliographically approved

Open Access in DiVA

No full text in DiVA

Authority records

Unemo, Magnus

Search in DiVA

By author/editor
Unemo, Magnus
By organisation
School of Medical SciencesÖrebro University Hospital
In the same journal
Molecular Immunology
Infectious Medicine

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 77 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf