Engineered toxin–intein antimicrobials can selectively target and kill antibiotic-resistant bacteria in mixed populations
| Autor: | Didier Mazel, Rocío López-Igual, Joaquín Bernal-Bayard, Alfonso Rodríguez-Patón, Jean-Marc Ghigo |
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| Přispěvatelé: | Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla. Departamento de Genética, Centre national de la recherche scientifique (CNRS). France, French Government Investissement d'Avenir. France, Agencia Estatal de Investigación. España, Comunidad Autónoma de Madrid, Fondation pour la Recherche Médicale. France, Plasticité du Génome Bactérien - Bacterial Genome Plasticity (PGB), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique des Biofilms, Institut Pasteur [Paris], Departamento de Inteligencia Artificial [UPM, Spain] (DIA), Universidad Politécnica de Madrid (UPM), This work was supported by the Institut Pasteur (to D.M. and J.-M.G.’s units), the Centre National de la Recherche Scientifique (grant no. CNRS-UMR 3525) (to D.M.), PLASWIRES 612146/FP7- FET-Proactive (to D.M.’s unit, A.R.-P.’s laboratory and for R.L.-I.’s salary), the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant no. ANR−10-LABX-62-IBEID to D.M. and J.-M.G.’s units), Spanish project TIN2016-81079-R (AEI/FEDER, EU) and Comunidad de Madrid (cofunded by FES and FEDER, EU) S2017/BMD-3691 project ingeMICS-CM (to A.R.-P.), the Fondation pour la Recherche Médicale (grant no. DBF20160635736 to D.M. and DEQ20140329508 to J.-M.G.). J.B.-B. was the recipient of a long-term post-doctoral fellowship from the Federation of European Biochemical Societies., We would like to thank E. Krin and M. Gugger for providing chromosome DNA for V. cholerae and V. fischeri, and N. punctiforme cells, respectively, and V. Burrus for V. cholerae O139. We thank G. Cambray and Z. Baharoglu for V. cholerae-GFP strain and RFP-containing plasmid, respectively. We thank S. Jin for her technical help. We thank also P. Escoll for assistance with microscopy, V. Briolat for providing us with the zebrafish and Artemias, A. Gomez-Losada for his help with the statistics treatment and S. Aguilar-Pierlé for helpful reading of the manuscript. We thank F. de la Cruz for his invaluable comments along the development of this work., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
MESH: Zebrafish/microbiology
MESH: Larva/microbiology Molecular biology MESH: Inteins Population MESH: Bacterial Toxins/pharmacology Biomedical Engineering Bioengineering medicine.disease_cause Applied Microbiology and Biotechnology Microbiology 03 medical and health sciences 0302 clinical medicine Plasmid Antibiotic resistance MESH: Vibrio cholerae/drug effects MESH: Plasmids MESH: Anti-Bacterial Agents/pharmacology medicine MESH: Animals education 030304 developmental biology 0303 health sciences education.field_of_study biology Pathogenic bacteria biology.organism_classification Antimicrobial Vibrio MESH: Anti-Bacterial Agents/chemistry 3. Good health [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology Vibrio cholerae Molecular Medicine MESH: Genetic Engineering 030217 neurology & neurosurgery Bacteria Biotechnology MESH: Toxin-Antitoxin Systems MESH: Artemia/microbiology |
| Zdroj: | Nature Biotechnology Nature Biotechnology, Nature Publishing Group, 2019, 37 (7), pp.755-760. ⟨10.1038/s41587-019-0105-3⟩ Nature Biotechnology, 2019, 37 (7), pp.755-760. ⟨10.1038/s41587-019-0105-3⟩ |
| ISSN: | 1087-0156 |
| DOI: | 10.1038/s41587-019-0105-3⟩ |
| Popis: | Targeted killing of pathogenic bacteria without harming beneficial members of host microbiota holds promise as a strategy to cure disease and limit both antimicrobial-related dysbiosis and development of antimicrobial resistance. We engineer toxins that are split by inteins and deliver them by conjugation into a mixed population of bacteria. Our toxin–intein antimicrobial is only activated in bacteria that harbor specific transcription factors. We apply our antimicrobial to specifically target and kill antibiotic-resistant Vibrio cholerae present in mixed populations. We find that 100% of antibiotic-resistant V. cholerae receiving the plasmid are killed. Escape mutants were extremely rare (10−6–10−8). We show that conjugation and specific killing of targeted bacteria occurs in the microbiota of zebrafish and crustacean larvae, which are natural hosts for Vibrio spp. Toxins split with inteins could form the basis of precision antimicrobials to target pathogens that are antibiotic resistant. Centre National de la Recherche Scientifique CNRS-UMR 3525 French Government Investissement d'Avenir ANR-10-LABX-62-IBEID Agencia Estatal de Investigación TIN2016-81079-R Comunidad de Madrid B2017/BMD-3691 Fondation pour la Recherche Médicale DBF20160635736, DEQ20140329508 |
| Databáze: | OpenAIRE |
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