# Innovative Strategies to Combat Antibiotic-resistant Infections

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2024 · $126,875

## Abstract

Abstract:
Antimicrobial resistance (AMR) represents a global public health crisis, with an estimated 1 0 million deaths per
year expected by 2050 without significant public health intervention and the development of new classes of
antibiotics. Towards combating this crisis, the parent grant funding of this supplement proposal has facilitated
the development of GmPcides, a novel class of synthetic antibiotics that target a wide range of Gram-positive
pathogens including vancomycin-resistant Enterococci (VRE), erythromycin and clindamycin-resistant
streptococci, methicillin-resistant and vancomycin-insensitive Staphylococcus aureus (MRSA, VISA;
respectively). Second generation GmPcides, including the lead compound PS757, have bactericidal activity
against stationary phase VRE as well as both exponential and stationary phase MRSA and have shown synergy
when combined with several classes of existing antibiotics. Further optimization of GmPcides have led to fourth
generation compounds with an sp3-rich 2-pyridone core with dramatically improved compound solubility with
equal or greater potency against VRE and MRSA than PS757. Treatment with lead 4th generation compounds
has also been shown to reduce ulcer size and time to healing in a murine skin and soft tissue infection model.
While resistance mutants can be selected against second generation compounds, repeated attempts to generate
resistance against fourth generation sp3-rich 2-pyridone GmPcides have proven unsuccessful. While good for
prospects of clinical efficacy, the lack of detectable resistance mutants has complicated identification of the
cellular targets of 4th generation compounds, which may be essential and difficult to assess with standard
approaches. This proposal will elucidate essential targets in MRSA of GmPcides in vitro and virulence
determinants that are important for survival to GmPcide challenge in the murine SSTI model. Understanding the
molecular interactions between GmPcides and their essential targets in vitro and during in vivo infection will allow
for further refinement of 4th generation GmPcides that improve their clinical effectiveness.

## Key facts

- **NIH application ID:** 11094234
- **Project number:** 3U19AI157797-04S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** SCOTT J. HULTGREN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $126,875
- **Award type:** 3
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11094234

## Citation

> US National Institutes of Health, RePORTER application 11094234, Innovative Strategies to Combat Antibiotic-resistant Infections (3U19AI157797-04S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/11094234. Licensed CC0.

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