# Discovery of Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $604,280

## Abstract

Project Summary/Abstract
Because of their favorable characteristics, β-lactams make up approximately 60% of antibiotic usage
worldwide. Bacterial resistance to β-lactam drugs, however, has been steadily increasing, posing a
significant threat to antibiotic therapy. The most common mechanism of resistance is
β-lactamase-catalyzed hydrolysis, which renders the antibiotics ineffective. An area of particular
concern is multi-drug resistant infections caused by Gram-negative rods; leaving few options for
treatment. Carbapenems are a class of β-lactam antibiotics that historically have been less
susceptible to the action of β-lactamases and have seen increased usage. A rising number of
bacterial infections acquired in hospital settings, however, are caused by carbapenem resistant
Enterobactericiae (CRE) pathogens. Enterobacteriaceae frequently become resistant to carbapenem
antibiotics by acquiring plasmid-encoded β-lactamases named carbapenemases. The three most
frequently encountered carbapenemases in clinics worldwide are KPC-2, NDM-1, and OXA-48. The
objective of this application is to utilize DNA-encoded chemical library technology to discover small
molecule inhibitors of these enzymes. This approach involves the creation of libraries of drug-like
molecules covalently attached to a unique DNA barcode that enables identification of binders for a
target in a large pool of compounds. DNA-encoded chemical libraries have been constructed at the
Center for Drug Discovery at Baylor College of Medicine that encode over 2 billion compounds,
allowing a screen of wide chemical space for novel, non-β-lactam inhibitors of these important
drug-resistance enzymes. In preliminary studies, we demonstrated the feasibility of the approach by
using a DNA-encoded chemical library to identify CDD-97, which inhibits OXA-48 with a Ki of 600 nM.
The X-ray structure of OXA-48 in complex with CDD-97 revealed it makes key interactions with
active site residues and medicinal chemistry studies have defined structure-activity relationships for
the molecule. DNA-encoded chemical library screens will be extended for the OXA-48, NDM-1 and
KPC-2 β-lactamases and identified inhibitors will be characterized with respect to potency of
inhibition, X-ray structure, spectrum of inhibition, and bioactivity versus bacteria. In addition,
medicinal chemistry methods will be used to optimize potency and accumulation of inhibitors in
bacteria. The proposed experiments have the potential to yield new, non-β-lactam, inhibitors and
provide insights into chemical scaffolds that are favorable for interaction with β-lactamases.

## Key facts

- **NIH application ID:** 10078242
- **Project number:** 5R01AI143832-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Timothy Palzkill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $604,280
- **Award type:** 5
- **Project period:** 2019-01-18 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078242

## Citation

> US National Institutes of Health, RePORTER application 10078242, Discovery of Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries (5R01AI143832-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10078242. Licensed CC0.

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