Recruiting the Immune System against Pathogenic Bacteria Using High-Affinity Chimeric Tags

The immune system plays a critical role in protecting the host against pathogens. However, mechanisms for evading the immune system have evolved in pathogens, altering their surface proteins or causing the expression of enzymes that interfere with the immune response. These strategies cause pathogens to escape detection and destruction by the immune system, thereby inducing severe infections. Thus, there is a critical need to develop new chemical tools to recruit the immune system against evading pathogens. Here, we describe a novel strategy for targeting pathogens, by labeling them with a chimeric agent that comprises a peptide bacterial binder, conjugated to an immune-protein tag that is recognizable by the complement system, thereby recruiting the immune system against the targeted pathogen. The chimeric tag was developed by conjugating the peptide bacterial binder with the C3b complement system activating protein. We showed that the chimeric C3b tag preserved its activity and was able to bind the C5 complement protein with strong binding affinity. Using this approach, we have demonstrated that the chimeric agent was able to eradicate 90% of complement-resistant <i>E. coli</i> bacterial cells. By showing enhancement of complement sensitivity in complement-resistant pathogens, this work demonstrates the basis for a new therapeutic approach for targeting pathogenic bacteria, which could open a new era in the development of selective and effective antimicrobial agents.