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Antibody-recruiting protein-catalyzed capture agents to combat antibiotic-resistant bacteria
Chem. Sci..2020;
Matthew N. Idso, a Ajay Suresh Akhade, a Mario L. Arrieta-Ortiz, a Bert T. Lai, b Vivek Srinivas, a James P. Hopkins Jr., a Ana Oliveira Gomes, a Naeha Subramanian, a Nitin Baligaa and James R. Heath *a
For MrkA binding assays, biotinylated PCCs were conjugated to the well surface, recombinant MrkA with a N-terminal 6xHis-SUMO-tag (MyBiosource, MBS1248970) was titrated at the desired concentration, and the primary antibody was His-tag antibody, pAb, Rabbit (Genscript, A00174) at a 1:5000 dilution.
Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting protein-catalyzed capture agents (ARPCCs), to address this challenge. We applied the combinatorial protein catalyzed capture agent (PCC) technology to identify macrocyclic peptide ligands against highly conserved surface protein epitopes of carbapenem-resistant Klebsiella pneumoniae, an opportunistic Gram-negative pathogen with drug resistant st... More
Antibiotic resistant infections are projected to cause over 10 million deaths by 2050, yet the development of new antibiotics has slowed. This points to an urgent need for methodologies for the rapid development of antibiotics against emerging drug resistant pathogens. We report on a generalizable combined computational and synthetic approach, called antibody-recruiting protein-catalyzed capture agents (ARPCCs), to address this challenge. We applied the combinatorial protein catalyzed capture agent (PCC) technology 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. Multi-omic data combined with bioinformatic analyses identified epitopes of the highly expressed MrkA surface protein of K. pneumoniae for targeting in PCC screens. The top-performing ligand exhibited high-affinity (EC50 50 nM) to full-length MrkA, and selectively bound to MrkAexpressing K. pneumoniae, but not to other pathogenic bacterial species. AR-PCCs that bear a hapten moiety promoted antibody recruitment to K. pneumoniae, leading to enhanced phagocytosis and phagocytic killing by macrophages. The rapid development of this highly targeted antibiotic implies that the integrated computational and synthetic toolkit described here can be used for the accelerated production of antibiotics against drug resistant bacteria.