# Developing a novel class of peptide antibiotics targeting carbapenem-resistant Gram-negative organisms

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $867,033

## Abstract

The alarming emergence of multidrug-resistant (MDR) pathogenic microorganisms worldwide and the lack of
next-generation portfolios of novel antimicrobials threaten human and public health. Therefore, it is a worldwide
priority to expedite the development of novel antimicrobial therapies to control MDR bacteria effectively. Natural
and synthetic antimicrobial peptides (AMPs) exhibit great potential as therapeutic agents because of their unique
modes of action in fast-killing bacteria through membrane permeation. However, several barriers to AMP
development limit its clinical application. This application aims to overcome current AMP limitations to develop a
safe and effective broad-spectrum antimicrobial against MDR Gram-negative bacterial infection. Our novel
peptide therapeutics A4-AMP antibiotics (A4X) is a new generation of computationally engineered AMPs
(eAMPs) derived from the antimicrobial motif, alpha-4, of a natural human host defense protein SPLUNC1 with
negligible toxicity to mammalian cells. The extensive results from our studies demonstrate that our current lead
candidate displays superior antibacterial activity to standard of care (SoC) antibiotics in over 500 clinical isolates
of difficult-to-kill MDR Gram-negative pathogens obtained from hospitals and the CDC & FDA Antibiotic
Resistance Isolate Bank. Our A4X lead also has a much lower tendency to develop resistance than SoC
antibiotics. The A4X lead is safe and well tolerated when intravenously administered to mice and rats, with a four
times higher maximum tolerated dosage than colistin, a last resort antibiotic, in mouse blood circulation.
 Moreover, we have demonstrated the efficacy of the A4X lead against Klebsiella pneumoniae and
Acinetobacter baumannii in mouse models of bacteremia and respiratory infection. In this project, we will carry
out preclinical and pre-IND non-clinical development activities and perform structure-activity relationship (SAR)
based optimization of the current A4X lead to advance the preclinical development and to determine the clinical
utility. We will extensively examine the safety, pharmacokinetic/pharmacodynamic, and efficacy of these novel
antimicrobial agents in small and large animals of the most effective A4X. The targeting bacteria are the MDR
strains of Gram-negative species on the CDC's urgent pathogen threats list and WHO's the most critical global
priority 1 pathogens list (carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumonia, and Escherichia
coli) and, including resistant strains to colistin. This proposal targets the urgent unmet global medical need for
novel antibiotics and addresses the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria in a
timely manner. Successful completion of these studies will have an enormous impact on developing a novel
class of antibiotics capable of fighting MDR "superbugs."

## Key facts

- **NIH application ID:** 10896281
- **Project number:** 5R01AI176537-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yuanpu Peter Di
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $867,033
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896281

## Citation

> US National Institutes of Health, RePORTER application 10896281, Developing a novel class of peptide antibiotics targeting carbapenem-resistant Gram-negative organisms (5R01AI176537-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896281. Licensed CC0.

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