{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Pitiot A"],"funding":["Luxembourg Government Ministry of Higher Education and Research","Institut National de la Santé et de la Recherche Médicale","National Research Fund","European Cooperation in Science and Technology","University of Tours"],"pagination":["105926"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12466147"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["120"],"pubmed_abstract":["<h4>Background</h4>Multidrug-resistant Pseudomonas aeruginosa raises major clinical concerns due to its capacity to cause a wide-array of infections in individuals with compromised immune defences and to withstand standard-of-care therapeutic treatments. Antibody-based approaches have proven to be efficient in the treatment of diverse infections. Here we propose an innovative approach harnessing the complement at the surface of bacteria for further killing.<h4>Methods</h4>We developed two Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) targeting the bacterium through a single-chain variable fragment directed against the exopolysaccharide Psl, and carrying one of two different effector functions, Factor H Related protein 1 (FHR1) or a Fc dimer. Each CoMiX was assessed in vitro for their antibacterial activity, and further evaluated in a mouse model of acute pneumonia.<h4>Findings</h4>Both CoMiX-FHR1 and CoMiX-Fc effectively deposit C1q (for CoMiX-Fc), C3b, and C5b9 at the surface of multidrug-resistant clinical isolates, promoting their direct killing and/or opsonisation and subsequent phagocytosis for CoMiX-Fc (p < 0.001). Both CoMiX synergise with amikacin and protect epithelial cells against P. aeruginosa-induced cytotoxicity. Importantly, CoMiX administered intranasal to acutely infected mice significantly improve their survival (p < 0.001) by reducing local bacterial burden through the higher induction of C3b (opsonisation) and C5a (neutrophils recruitment and activation) and by decreasing lung inflammation.<h4>Interpretation</h4>Our proof-of-concept demonstrates the efficient, direct and indirect killing of P. aeruginosa by the complement, highlighting the therapeutic potential of CoMiX to combat multidrug-resistant bacteria.<h4>Funding</h4>Luxembourg National Research Fund, Ministry of Higher Education and Research of Luxembourg, COST action CA21145 EURESTOP, Institut National de la Santé et de la Recherche Médicale, and Tours University."],"journal":["EBioMedicine"],"pubmed_title":["Directed-complement killing of Pseudomonas aeruginosa protects against lethal pneumonia."],"pmcid":["PMC12466147"],"funding_grant_id":["CA21145","C22/BM/17380893/PSEUDO","LIH GBB 98000005"],"pubmed_authors":["Zimmer J","Iserentant G","Seguin-Devaux C","Chesnay A","Dervillez X","Si-Tahar M","Servais JY","Pitiot A","Fouquenet D","Briard B","Brandus B","Rassam P","Desoubeaux G","Mely Y","Rolin C","Richert L"],"additional_accession":[]},"is_claimable":false,"name":"Directed-complement killing of Pseudomonas aeruginosa protects against lethal pneumonia.","description":"<h4>Background</h4>Multidrug-resistant Pseudomonas aeruginosa raises major clinical concerns due to its capacity to cause a wide-array of infections in individuals with compromised immune defences and to withstand standard-of-care therapeutic treatments. Antibody-based approaches have proven to be efficient in the treatment of diverse infections. Here we propose an innovative approach harnessing the complement at the surface of bacteria for further killing.<h4>Methods</h4>We developed two Complement-activating Multimeric immunotherapeutic compleXes (CoMiX) targeting the bacterium through a single-chain variable fragment directed against the exopolysaccharide Psl, and carrying one of two different effector functions, Factor H Related protein 1 (FHR1) or a Fc dimer. Each CoMiX was assessed in vitro for their antibacterial activity, and further evaluated in a mouse model of acute pneumonia.<h4>Findings</h4>Both CoMiX-FHR1 and CoMiX-Fc effectively deposit C1q (for CoMiX-Fc), C3b, and C5b9 at the surface of multidrug-resistant clinical isolates, promoting their direct killing and/or opsonisation and subsequent phagocytosis for CoMiX-Fc (p < 0.001). Both CoMiX synergise with amikacin and protect epithelial cells against P. aeruginosa-induced cytotoxicity. Importantly, CoMiX administered intranasal to acutely infected mice significantly improve their survival (p < 0.001) by reducing local bacterial burden through the higher induction of C3b (opsonisation) and C5a (neutrophils recruitment and activation) and by decreasing lung inflammation.<h4>Interpretation</h4>Our proof-of-concept demonstrates the efficient, direct and indirect killing of P. aeruginosa by the complement, highlighting the therapeutic potential of CoMiX to combat multidrug-resistant bacteria.<h4>Funding</h4>Luxembourg National Research Fund, Ministry of Higher Education and Research of Luxembourg, COST action CA21145 EURESTOP, Institut National de la Santé et de la Recherche Médicale, and Tours University.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Oct","modification":"2026-06-30T03:22:56.305Z","creation":"2026-06-30T03:15:58.291Z"},"accession":"S-EPMC12466147","cross_references":{"pubmed":["40961506"],"doi":["10.1016/j.ebiom.2025.105926"]}}