Antibody-recruiting protein-catalyzed capture agents to combat antibiotic-resistant bacteria.

Chemical Science
Matthew N IdsoJames R Heath

Abstract

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 (AR-PCCs), 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 MrkA-expressing 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 de...Continue Reading

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Citations

Apr 15, 2021·Annual Review of Biomedical Engineering·Ming LeiKyongbum Lee
Aug 21, 2021·Bioconjugate Chemistry·Maruthi Kumar NarayanamJennifer M Murphy

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Datasets Mentioned

BETA
GSE71754
MBS1248970

Methods Mentioned

BETA
enzyme-linked immunosorbent assay
enzyme-linked immunosorbent assays
ELISA
ELISAs
flow cytometry

Software Mentioned

BlastP
MAFFT
BLAST
NetsurfP
Jalview
BepiPred
EMBOSS Transeq
FlowJo

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