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

Autor: Idso MN; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Akhade AS; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Arrieta-Ortiz ML; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Lai BT; Indi Molecular, Inc. 6162 Bristol Parkway Culver City CA 90230 USA., Srinivas V; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Hopkins JP Jr; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Gomes AO; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Subramanian N; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Baliga N; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org., Heath JR; Institute for Systems Biology 401 Terry Ave North Seattle 98109 USA jim.heath@isbscience.org.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2020 Feb 12; Vol. 11 (11), pp. 3054-3067. Date of Electronic Publication: 2020 Feb 12.
DOI: 10.1039/c9sc04842a
Abstrakt: 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 (EC 50 ∼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.
Competing Interests: J.R.H is a co-founder and B.T.L. is an employee of Indi Molecular Inc., which seeks to commercialize PCC technology.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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