# Novel selective substituted aminofurazans kinase inhibitors for Drug resistant Bacteria

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2020 · —

## Abstract

Antibiotic resistant bacteria are a major threat to human health. Each year in the United States,
approximately 2 million people are infected with bacteria that are resistant to antibiotics resulting in at least
23,000 deaths. The development of novel antibiotics is needed. However, de novo antibiotic development is
resource intensive. Given the poor return on investment, major pharmaceutical companies have significantly
decreased antibiotic Research and Development efforts. Academic labs generally do not have access to
compounds and sufficient data for rationale design. Veterans who undergo surgical procedures for trauma,
including head trauma, are vulnerable to multiple surgical infection, sometimes with organisms that are unlikely
to ever represent an attractive target for pharmaceutical companies.
 Antibiotic development that capitalizes on existing drug designwork conducted by industry, may avoid
some of the expensive missteps due to poor pharmacologic properties that can inadvertently arise in the lead
selection. Our approach uses structure-based computational modeling to repurpose drugs as antibiotics.
Previous work in our lab demonstrated that inhibition of a Listeria kinase, belonging to a family of Penicillin
binding And Serine/Threonine kinase Associated (PASTA) proteins, can sensitize the bacteria to beta-lactam
antibiotics. Bacterial Serine/Threonine kinases are signal transducers and our work suggests they are a novel
drug development target. While PASTA kinases are common in some gram-positive bacteria, we found there is
drug selectivity, not only between human and bacterial kinases, but also between bacterial kinases. We are
targeting the subset of PASTA kinase containing bacteria with a large back pocket. We have already obtained
a crystal structure of our target bacterial kinase (PknB) with a lead compound demonstrating this pocket. This
information enables us to specifically modify the lead to both increase potency and maximize selectivity using
previously defined structure activity relationships with human kinases. Furthermore, our atomic resolution drug:
target structure will guide us on regions of the drug that can be modified to explicitly test Lipinski's rules for
drug development and determine if they should be modified for antibiotic drug development. In this proposal,
we will build on our existing work with the following Specific Aims:
 Aim 1: Design, synthesize, and test both biochemically and microbiologically novel aminofurazan
kinase inhibitors that exploit the uniquely shaped back pocket of some of the PknB family of kinases.
Aim 2: Test the toxicity of these novel kinase inhibitors, as well as determine the effectiveness of
 combined beta lactam antibiotics with kinase inhibition in an animal model (Danio rerio). We will
 analyze the effect of our kinase inhibitors on both a panel of human kinases as well as on
 embryogenesis and fertility in zebrafish.
When this work is complete, we will have generated data on ho...

## Key facts

- **NIH application ID:** 9859333
- **Project number:** 5I01BX004089-03
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** ROBERT T STRIKER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859333

## Citation

> US National Institutes of Health, RePORTER application 9859333, Novel selective substituted aminofurazans kinase inhibitors for Drug resistant Bacteria (5I01BX004089-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9859333. Licensed CC0.

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