Chemical Science Publishes Article on Protein-Catalyzed Capture Agents that Combat Antibiotic Resistant Bacteria

CULVER CITY, CA, March 3, 2020 - Indi Molecular today announced that Chemical Science has published an article on a combined computational and synthetic approach for developing antibiotics against drug resistant pathogens called antibody-recruiting protein-catalyzed capture agents (AR-PCCs). The article was written by researchers from the Institute for Systems Biology and Indi Molecular.

“AR-PCCs represent a promising all-synthetic molecular platform that can be rapidly designed, built and deployed against resistant microbes,” said Albert A. Luderer, Ph.D., chief executive and co-founder, Indi Molecular. “We believe this technology could be successfully used to develop effective therapeutics for a broad range of antibiotic resistant bacteria.”

The article describes how PCC technology was applied to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic Gram-negative pathogen with drug-resistant strains that frequently cause hospital-acquired infections. Multi-omic data and bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing PCC ligand exhibited high affinity (EC50 ~50 nM) to MrkA protein and selectively bound to MrkA-expressing K. pneumoniae, but not to other pathogenic bacterial species. The hapten 2,4-dinitrophenyl (DNP) was incorporated into the PCC as an antibody-recruiting (AR) label for eliciting a targeted immune response. These AR-PCCs were shown to promote antibody recruitment to K. pneumoniae, leading to enhanced phagocytosis and phagocytic killing of the pathogen by innate immune cells. Experiments are currently underway to study the efficacy of AR-PCCs in mouse models. The approaches developed for targeting K. pneumoniae should be broadly adaptable to targeting other antibiotic resistant extracellular pathogens. This versatility also could be leveraged for development of cocktails of AR-PCCs that simultaneously target several conserved surface epitopes on a single pathogen, to facilitate complete clearance of bacterial populations that exhibit heterogenous surface protein expression.

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