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Antibody-Recruiting Protein-Catalyzed Capture Agents to Combat Antibiotic-Resistant Bacteria

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 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 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.

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Supplementary files

Article information


Submitted
25 Sep 2019
Accepted
09 Feb 2020
First published
12 Feb 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Accepted Manuscript
Article type
Edge Article

Antibody-Recruiting Protein-Catalyzed Capture Agents to Combat Antibiotic-Resistant Bacteria

M. N. N. Idso, A. S. Akhade, M. L. Arrieta-Ortiz, B. T. Lai, V. Srinivas, J. P. Hopkins, A. Oliveira Gomes, N. Subramanian, N. Baliga and J. R. Heath, Chem. Sci., 2020, Accepted Manuscript , DOI: 10.1039/C9SC04842A

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