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Updated: Jul 8, 2025
The Use of a β-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions
Published on: February 1, 2018
Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library
Suhyeorn Park1, Jiayi Fan1, Srinivas Chamakuri2
1Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, Texas 77030, United States.
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 106 compounds, each containing a carboxylic acid or a tetrazole as an enzyme recognition element, was designed, constructed, and used to identify OXA-48 and NDM-1 inhibitors with micromolar to nanomolar potency. Further optimization led to NDM-1 inhibitors with increased potencies and biological activities. This work demonstrates that the carboxylate-binding pocket-targeting DECL, designed based on substrate binding information, aids in inhibitor identification and led to the discovery of novel non-β-lactam pharmacophores for the development of β-lactamase inhibitors for enzymes of different structural and mechanistic classes.
Insights
Researchers discovered novel inhibitors for carbapenem-resistant bacteria using DNA-encoded chemical library (DECL) technology. This approach targets the β-lactamase enzyme
Area of Science:
- Microbiology
- Medicinal Chemistry
- Drug Discovery
Background:
- Beta-lactamase enzymes confer bacterial resistance to beta-lactam antibiotics.
- OXA-48 and NDM-1 beta-lactamases provide resistance to carbapenems, posing a significant public health risk.
- Novel inhibitors are crucial to combatting infections caused by resistant bacteria.
Purpose of the Study:
- To discover novel inhibitors of beta-lactamase enzymes, specifically OXA-48 and NDM-1.
- To utilize DNA-encoded chemical library (DECL) technology for inhibitor discovery.
- To develop non-beta-lactam pharmacophores targeting the conserved carboxylate-binding pocket of beta-lactamases.
Main Methods:
- Designed and constructed a DNA-encoded chemical library (DECL) of 10^6 compounds.
- Targeted the conserved carboxylate-binding pocket of beta-lactamases based on enzyme-substrate binding interactions.
- Screened the DECL to identify inhibitors of OXA-48 and NDM-1 beta-lactamases.
Main Results:
- Identified OXA-48 and NDM-1 beta-lactamase inhibitors with micromolar to nanomolar potency.
- Achieved further optimization of NDM-1 inhibitors, enhancing their potency and biological activity.
- Discovered novel non-beta-lactam pharmacophores through the DECL approach.
Conclusions:
- DNA-encoded chemical library (DECL) technology is effective for discovering beta-lactamase inhibitors.
- Targeting the carboxylate-binding pocket is a viable strategy for broad-spectrum beta-lactamase inhibition.
- The identified novel pharmacophores offer potential for developing new antibiotics against resistant bacteria.
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