Development of an antibody fused with an antimicrobial peptide targetingPseudomonas aeruginosa:a new approach to prevent and treat bacterial infections

Abstract

AbstractThe increase of emerging drug resistant Gram-negative bacterial infections is of global concern. In addition, there is growing recognition that compromising the microbiota, through the use of broad spectrum antibiotics, may affect patient health in the long term. Therefore, there is the need to develop new -cidal strategies to combat Gram-negative infections that would consider these specific issues. In this study, we report and characterize one such approach, the antibody-drug conjugates (ADCs) that combine (i) targeting a specific pathogenic organism through a monoclonal antibody with (ii) the high killing activity of antimicrobial peptides. We focused on a major pathogenic Gram-negative bacterium associated with antibacterial resistance:Pseudomonas aeruginosaand designed an ADC by fusing an antimicrobial peptide at the C-terminal end of the VHand/or VL-chain of a monoclonal antibody, VSX, that targets the core ofP. aeruginosalipopolysaccharide (LPS). This ADC demonstrated appropriately minimal levels of toxicity to mammalian cells and rapidly killsP. aeruginosastrains through several mechanisms while protecting mice fromP. aeruginosalung infection when administered therapeutically. Furthermore, we found that the ADC was synergistic with several classes of antibiotics. This approach described in this study may result in a widely useful strategy to target specific pathogenic microorganisms without augmenting further antibiotic resistance.Author SummaryThe increasing of emerging drug resistant bacterial infections is a worldwide issue and infections caused by antibiotic resistant Gram-negative pathogens are particularly concerning. In addition, there is now growing recognition that disruption of the microbiota, through the use of broad spectrum antibiotics, may affect patient health in the long term. Therefore, there is the need to develop new -cidal strategies to combat Gram-negative infections while preserving the microbiota and also avoid enhancement of antibiotic resistance. We report and characterize here one such approach by using a specific monoclonal antibody associated with the potent killing activity of antimicrobial peptides in the form of an antibody-drug conjugate (ADC). The selected pathogenic bacterium wasPseudomonas aeruginosa,that presents numerous markers for both innate and acquired antibiotic resistance. The ADC lacked significant cytotoxicity against mammalian cells and was shown to be effective bothin vitroandin vivoagainstP. aeruginosa.