# NMR Fragment-based Design of New b-lactamase Inhibitors

> **NIH NIH R21** · BROWN UNIVERSITY · 2024 · $199,375

## Abstract

NMR Fragment-based Design of New β-lactamase Inhibitors.
SUMMARY
A rapid and widespread increase in antimicrobial resistance over the past few decades has seriously threatened
our capability to treat bacterial infections that may persist following treatment with last-resort antibiotics such as
carbapenems and polymyxins. Given bacterial β-lactamase enzymes can degrade β-lactam antibiotics, β-
lactamase inhibitors have been widely sought to improve the efficacy of this antibiotics class. Since the majority
of recently approved antimicrobial agents for Gram-negative pathogens are β-lactam + β-lactamase inhibitor
combinations, the validity of this approach is widely accepted. However, microbial β-lactamases are constantly
evolving into new forms that can evade the activity of β-lactamase inhibitors. Nuclear magnetic resonance (NMR)
spectroscopy can generate high-resolution structural and dynamics information on proteins like β-lactamases
and map atomic details of interacting chemical entities like β-lactamase inhibitors. These structural details create
new opportunities such as fragment-based drug discovery (FBDD). These techniques are at the forefront of
many research programs and have proven successful in antimicrobial drug development. The fragment-based
approach is distinct from high-throughput screening of drug libraries and has yet to be applied to β-lactamase
inhibitor development. Here our objective is to expand the use of FBDD and discover new chemistry by designing
inhibitors against β-lactamases TEM-1, SHV-1, PDC-3, and OXA-40. The specific goals for this project are to
develop new inhibitors based on the diazabicyclooctane scaffold and to generate detailed NMR maps of this set
of β-lactamases. Backed by our preliminary data that has identified 69 TEM-1 interacting fragments, our multi-
faceted approach relies on structural biology, medicinal chemistry, and microbiology approaches to advance the
fragment-based methodology for the identification of new β-lactamase inhibitors. These inhibitors will be
designed around a drug scaffold that targets the active site of broad-spectrum β-lactamases, therefore our
approach should result in the identification of potent inhibitors active against a broad spectrum of resistant
bacteria. Moreover, we will perform NMR relaxation studies to explore allosteric mechanisms in β-lactamases.
Public Health Impact: The World Health Organization has given the highest priority to anti-microbial research
on the Gram-negative bacteria genera Acinetobacter and Pseudomonas, as well as specific species of
Enterobacterales in which extensively-drug resistant strains are increasingly emerging. These resistant strains
can cause systemic infection and may not respond to known antibiotics that are rendered ineffective due to
specialized enzymes produced by the bacteria that degrade and thereby confer resistance to important classes
of antibiotics such as β-lactams. The goal of this project is to develop a structure-based me...

## Key facts

- **NIH application ID:** 10888590
- **Project number:** 1R21AI178257-01A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Mandar T Naik
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $199,375
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888590

## Citation

> US National Institutes of Health, RePORTER application 10888590, NMR Fragment-based Design of New b-lactamase Inhibitors (1R21AI178257-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10888590. Licensed CC0.

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