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Serum complement ac...
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Bettoni, SerenaDepartment of Translational Medicine, Lund University, Malmö, Sweden
(författare)
Serum complement activation by C4BP-IgM fusion protein can restore susceptibility to antibiotics in Neisseria gonorrhoeae
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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Elsevier,2022
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Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:oru-98827
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https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-98827URI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:vet swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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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.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Maziarz, KarolinaDepartment of Translational Medicine, Lund University, Malmö, Sweden
(författare)
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Stone, M. Rhia L.Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD, Australia
(författare)
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Blaskovich, Mark A. T.Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD, Australia
(författare)
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Potempa, JanFaculty of Biochemistry, Biophysics and Biotechnology, Jagiel- lonian University, Krakow, Poland. Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Louisville KY, United States
(författare)
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Bazzo, Maria LuizaMolecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianopolis, Brazil
(författare)
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Unemo, Magnus,1970-Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,World Health Organization (WHO) Collaborating Centre for Gonorrhoea and other STIs(Swepub:oru)muo
(författare)
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Ram, SanjayDepartment of Medicine, Division of Infectious Diseases, Univer- sity of Massachusetts Medical School, Worcester MA, United States
(författare)
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Blom, Anna M.Department of Translational Medicine, Lund University, Malmö, Sweden
(författare)
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Department of Translational Medicine, Lund University, Malmö, SwedenCentre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, Brisbane QLD, Australia
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Molecular Immunology: Elsevier141, s. 215-2150161-58901872-9142
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Bettoni, Serena
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Maziarz, Karolin ...
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Stone, M. Rhia L ...
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Blaskovich, Mark ...
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Potempa, Jan
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Bazzo, Maria Lui ...
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Unemo, Magnus, 1 ...
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Ram, Sanjay
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Blom, Anna M.
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Örebro universitet