Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections.
The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011612 |
| _version_ | 1797674073393725440 |
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| author | Kenneth Johnson James C Delaney Thomas Guillard Fany Reffuveille Jennifer Varin-Simon Kai Li Andrew Wollacott Eric Frapy Surin Mong Hamid Tissire Karthik Viswanathan Faycal Touti Gregory J Babcock Zachary Shriver Bradley L Pentelute Obadiah Plante David Skurnik |
| author_facet | Kenneth Johnson James C Delaney Thomas Guillard Fany Reffuveille Jennifer Varin-Simon Kai Li Andrew Wollacott Eric Frapy Surin Mong Hamid Tissire Karthik Viswanathan Faycal Touti Gregory J Babcock Zachary Shriver Bradley L Pentelute Obadiah Plante David Skurnik |
| author_sort | Kenneth Johnson |
| collection | DOAJ |
| description | The increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new bactericidal strategies to combat Gram-negative infections that would address these specific issues. In this study, we report and characterize one such approach, an antibody-drug conjugate (ADC) that combines (i) targeting the surface of a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of an antimicrobial peptide. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa. To target this organism, we designed an ADC by fusing an antimicrobial peptide to the C-terminal end of the VH and/or VL-chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide. This ADC demonstrates appropriately minimal levels of toxicity against mammalian cells, rapidly kills P. aeruginosa strains, and protects mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study might result in a broadly useful strategy for targeting specific pathogenic microorganisms without further augmenting antibiotic resistance. |
| first_indexed | 2024-03-11T21:53:51Z |
| format | Article |
| id | doaj.art-8b565cd43cf347e9bb67ff626b5234bf |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-11T21:53:51Z |
| publishDate | 2023-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-8b565cd43cf347e9bb67ff626b5234bf2023-09-26T05:31:12ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-09-01199e101161210.1371/journal.ppat.1011612Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections.Kenneth JohnsonJames C DelaneyThomas GuillardFany ReffuveilleJennifer Varin-SimonKai LiAndrew WollacottEric FrapySurin MongHamid TissireKarthik ViswanathanFaycal ToutiGregory J BabcockZachary ShriverBradley L PenteluteObadiah PlanteDavid SkurnikThe increase in emerging drug resistant Gram-negative bacterial infections is a global concern. In addition, there is growing recognition that compromising the microbiota through the use of broad-spectrum antibiotics can impact long term patient outcomes. Therefore, there is the need to develop new bactericidal strategies to combat Gram-negative infections that would address these specific issues. In this study, we report and characterize one such approach, an antibody-drug conjugate (ADC) that combines (i) targeting the surface of a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of an antimicrobial peptide. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance: Pseudomonas aeruginosa. To target this organism, we designed an ADC by fusing an antimicrobial peptide to the C-terminal end of the VH and/or VL-chain of a monoclonal antibody, VSX, that targets the core of P. aeruginosa lipopolysaccharide. This ADC demonstrates appropriately minimal levels of toxicity against mammalian cells, rapidly kills P. aeruginosa strains, and protects mice from P. aeruginosa lung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study might result in a broadly useful strategy for targeting specific pathogenic microorganisms without further augmenting antibiotic resistance.https://doi.org/10.1371/journal.ppat.1011612 |
| spellingShingle | Kenneth Johnson James C Delaney Thomas Guillard Fany Reffuveille Jennifer Varin-Simon Kai Li Andrew Wollacott Eric Frapy Surin Mong Hamid Tissire Karthik Viswanathan Faycal Touti Gregory J Babcock Zachary Shriver Bradley L Pentelute Obadiah Plante David Skurnik Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. PLoS Pathogens |
| title | Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. |
| title_full | Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. |
| title_fullStr | Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. |
| title_full_unstemmed | Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. |
| title_short | Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections. |
| title_sort | development of an antibody fused with an antimicrobial peptide targeting pseudomonas aeruginosa a new approach to prevent and treat bacterial infections |
| url | https://doi.org/10.1371/journal.ppat.1011612 |
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