Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library

Authors

Suhyeorn Park
Jiayi Fan
Srinivas Chamakuri
Murugesan Palaniappan
Kiran Sharma
Xuan Qin
Jian Wang
Zhi Tan
Allison Judge
Liya Hu
Banumathi Sankaran
Feng Li
B V Venkataram Prasad
Martin M Matzuk
Timothy Palzkill

Publication Date

1-11-2024

Journal

Journal of Medicinal Chemistry

DOI

10.1021/acs.jmedchem.3c01834

PMID

38117688

PMCID

PMC11489902

PubMedCentral® Posted Date

1-11-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

beta-Lactamase Inhibitors, Anti-Bacterial Agents, beta-Lactamases, beta-Lactams, Penicillins, DNA, Microbial Sensitivity Tests

Abstract

β-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important β-lactam class of antibiotics. The OXA-48 and NDM-1 β-lactamases cause resistance to the last-resort β-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel β-lactamase inhibitors. We exploited the β-lactamase enzyme-substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all β-lactamases. A library of 10

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