Complement-dependent outer membrane perturbation sensitizes Gram-negative bacteria to Gram-positive specific antibiotics

Scientific Reports
Dani A C HeesterbeekBart W Bardoel

Abstract

Gram-negative bacteria are refractory to the action of many antibiotics due to their impermeable outer membrane. An important player of the immune system is the complement system, a protein network in serum that directly kills Gram-negative bacteria through pore-formation by the Membrane Attack Complexes (MAC). We here show that the MAC rapidly perforates the outer membrane but that inner membrane damage, which is essential for killing, is relatively slow. Importantly, we demonstrate that MAC-induced outer membrane damage sensitizes Gram-negative bacteria to otherwise ineffective, Gram-positive-specific, antimicrobials. Synergy between serum and nisin was observed for 22 out of 53 tested Gram-negative clinical isolates and for multi-drug resistant (MDR) blood isolates. The in vivo relevance of this process is further highlighted by the fact that blood sensitizes a MDR K. pneumoniae strain to vancomycin. Altogether, these data imply that antibiotics that are considered ineffective to treat infections with Gram-negatives may have different functional outcomes in patients, due to the presence of the complement system.

References

May 1, 1978·Antimicrobial Agents and Chemotherapy·B S DutcherR K Cunningham
Dec 1, 1991·Applied and Environmental Microbiology·K A StevensT R Klaenhammer
Jan 1, 1986·Annual Review of Immunology·H J Müller-Eberhard
Oct 1, 1982·Antimicrobial Agents and Chemotherapy·R Nakae, T Nakae
Jul 2, 1998·Applied and Environmental Microbiology·P LebaronN Parthuisot
Feb 4, 2003·The Journal of Antimicrobial Chemotherapy·Evangelos J Giamarellos-BourboulisHelen Giamarellou
Nov 3, 2004·Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America·Erika M C D'Agata
Feb 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Miles A NunnPatricia A Nuttall
Mar 15, 2006·Nature Reviews. Drug Discovery·Eefjan Breukink, Ben de Kruijff
Oct 5, 2007·Expert Review of Anti-infective Therapy·Julián Andrés TorresJohn P Quinn
Dec 23, 2008·Biochimica Et Biophysica Acta·Anne H Delcour
May 11, 2010·Cold Spring Harbor Perspectives in Biology·Thomas J SilhavySuzanne Walker
Mar 26, 2011·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Laura Freire-MoranUNKNOWN ECDC-EMA Working Group
May 10, 2011·FEBS Letters·Jean-Michel BollaJean-Marie Pagès
Sep 5, 2012·Biological Chemistry·Michal Potempa, Jan Potempa
Oct 31, 2013·The Journal of Antibiotics·Neha GargWilfred A van der Donk
Nov 21, 2013·The Lancet Infectious Diseases·Ramanan LaxminarayanOtto Cars
Feb 1, 2014·Metallomics : Integrated Biometal Science·Gaëtan L A Mislin, Isabelle J Schalk
Jun 1, 2014·Drug Discovery Today·Michael S Kinch, Eric Patridge
Mar 19, 2015·Scientific Reports·Joanna JammalAmram Mor
Dec 10, 2015·The Journal of Biological Chemistry·Harsha BajajMathias Winterhalter
Sep 15, 2016·ACS Infectious Diseases·Venkateswarlu YarlagaddaJayanta Haldar
Oct 27, 2016·Immunological Reviews·Bryan Paul MorganDoryen Bubeck
May 11, 2017·Nature·Michelle F RichterPaul J Hergenrother
Jul 3, 2018·ACS Infectious Diseases·Silvia Acosta-GutiérrezMatteo Ceccarelli
Sep 29, 2018·Nature Communications·João Medeiros-SilvaMarkus Weingarth

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Citations

Aug 28, 2019·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Dennis J DoorduijnDani A C Heesterbeek
Jun 23, 2020·PLoS Pathogens·Dennis J DoorduijnSuzan H M Rooijakkers
Nov 17, 2020·Frontiers in Cellular and Infection Microbiology·Ann-Britt Schäfer, Michaela Wenzel
Jan 29, 2021·Microbiology and Molecular Biology Reviews : MMBR·Elisabet Bjanes, Victor Nizet
Mar 11, 2020·Trends in Immunology·Vincent P van HensbergenLhousseine Touqui
Apr 10, 2020·ACS Infectious Diseases·Toni A NagyCorrella S Detweiler
Feb 23, 2021·Environmental Research·Chaoyu TongJianye Zhang
Mar 22, 2020·Molecular Immunology·Deepak KumarSherry D Fleming
Feb 10, 2020·Current Opinion in Microbiology·Corrella S Detweiler
Dec 23, 2021·Scientific Reports·Verena VogelBarbara Spellerberg

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Methods Mentioned

BETA
flow cytometry

Software Mentioned

FIJI

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