Journal Article

Development of an antibody fused with an antimicrobial peptide targeting Pseudomonas aeruginosa: A new approach to prevent and treat bacterial infections

Li, Kai, Babcock, Gregory J., Delaney, James C., Plante, Obadiah, Frapy, Eric, Varin-Simon, Jennifer, Reffuveille, Fany, Skurnik, David, Touti, Faycal, Guillard, Thomas, Johnson, Kenneth, Viswanathan, Karthik, Shriver, Zachary, Pentelute, Bradley L., Tissire, Hamid, Wollacott, Andrew, Mong, Surin

2023

Overview

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 V H and/or V L -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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibacterial agents / Antibiotic resistance / Antibiotics / Antibodies / Antiinfectives and antibacterials / Antimicrobial agents / Antimicrobial peptides / Bacteria / Bacterial diseases / Bacterial infections / Biological products / Biology and Life Sciences / Bronchopulmonary infection / Cells / Drug dosages / Drug resistance / Drug resistance in microorganisms / Gram-negative bacteria / Granulocytes / Health aspects / Infection / Infection control / Infections / Leukocytes / Life Sciences / Lipopolysaccharides / Mammalian cells / Medicine and Health Sciences / Microbiota / Microbiota (Symbiotic organisms) / Microorganisms / Monoclonal antibodies / Pathogens / Peptides / Prevention / Pseudomonas aeruginosa / Public health / Research and Analysis Methods / Toxicity / Viral antibodies