(182g) An All-Synthetic Platform for Highly-Targeted Immune-Activating Antibiotics Against Resistant Bacteria

The Centers for Disease Control and Prevention anticipates that antibiotic resistant pathogens will claim 10 million lives annually by 2050. This dire projection is driven by the lack of new antibiotics, which have moreover become challenging to discover by conventional techniques. We have developed a versatile new class of narrow-spectrum antibiotics, called immune-activating protein-catalyzed capture agents (IA-PCCs), that can be rapidly developed against designated resistant bacterial pathogens. IA-PCCs are bispecific compounds that comprise of an epitope-specific peptide ligand (the PCC) that binds the bacterium, and a hapten moiety that promotes immune clearance of the pathogen. Demonstrated here is the development of IA-PCCs against two resistant bacteria of high clinical significance: carbapenem-resistant Klebsiella pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). Integrated bioinformatics and multi-omic data analyses guided the judicious selection of abundant pathogen-specific epitope targets on the surface of each bacterium. Subsequent PCC screens against the selected epitopes yielded several macrocyclic ligands that exhibited high avidity to their molecular targets as well as whole K. pneumoniae and MRSA bacterial cells, as determined by enzyme-linked immunosorbent assays. Top-performing PCCs were conjugated with an antibody-recruiting hapten, dinitrophenyl (DNP), to form an IA-PCC. This IA-PCC promoted the recruitment of antibodies to bacterial surfaces and enhanced opsonophagocytic killing of resistant pathogen by murine bone-marrow derived macrophages. Variations on the immune-activating moiety are explored, by replacing the antibody-recruiting DNP label with molecular tags that directly activate immune cells, including formylated peptides, toll-like receptor agonists, and synthetic peptides. Lead IA-PCCs are subjected to medicinal-chemistry type iterations to improve physicochemical properties associated with in vivo performance, ultimately arriving at compounds ready for translation in vivo. In vivo mouse models to test IA-PCC efficacy are ongoing. The IA-PCC platform has emerged as a promising and general platform to address antibiotic resistance.