An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities.
Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.
Departamento de Biologia, Instituto de Ciências Biológicas, Programa de pós-graduação em Genética e Biotecnologia, Universidade Federal de Juiz de Fora, Juiz de Fora-MG, Brazil.|S-Inova Biotech, Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil.
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ON
Silva
Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Harvard Biophysics Program, Harvard University, Boston, Massachusetts, United States of America.|The Center for Microbiome Informatics and Therapeutics, Cambridge, Massachusetts, United States of America.
C
C
de la Fuente-Núñez
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
E F
EF
Haney
Centro de Análises Proteômicas e Bioquímicas, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil.|Programa de Pós-graduação em Patologia Molecular, Universidade de Brasília, Brasília, Brazil.
I C M
IC
Fensterseifer
S-Inova Biotech, Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil.
S M
SM
Ribeiro
Programa de Pós-graduação em Patologia Molecular, Universidade de Brasília, Brasília, Brazil.
W F
WF
Porto
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
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P
Brown
Curso de Odontologia, Universidade Católica de Brasília, Brazil.
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C
Faria-Junior
Centro de Análises Proteômicas e Bioquímicas, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil.|Curso de Odontologia, Universidade Católica de Brasília, Brazil.|Pós-graduação em Ciências da Saúde, Universidade de Brasília, Brazil.
T M B
TM
Rezende
S-Inova Biotech, Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil.
S E
SE
Moreno
Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Department of Biological Engineering, and Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.|Harvard Biophysics Program, Harvard University, Boston, Massachusetts, United States of America.|The Center for Microbiome Informatics and Therapeutics, Cambridge, Massachusetts, United States of America.
T K
TK
Lu
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
R E W
RE
Hancock
Departamento de Biologia, Instituto de Ciências Biológicas, Programa de pós-graduação em Genética e Biotecnologia, Universidade Federal de Juiz de Fora, Juiz de Fora-MG, Brazil.|S-Inova Biotech, Pós-graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, MS, Brazil.|Centro de Análises Proteômicas e Bioquímicas, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil.|Programa de Pós-graduação em Patologia Molecular, Universidade de Brasília, Brasília, Brazil.
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OL
Franco
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy; D001798:Blood Proteins / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology*; D056747:Immunomodulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000067996:RAW 264.7 Cells
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D007155:Immunologic Factors; D010455:Peptides; C106713:clavanin A