# Novel Biamyxins targeting multidrug resistant Gram-negative bacterial infections

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $802,798

## Abstract

Gram-negative (G-) bacteria are leading causes of healthcare-associated infections (HAIs). According to the
U.S. Department of Health and Human Services, over 1 million HAIs occur across the health care system every
year in the US, and hospital-acquired HAIs alone are responsible for $28 to $33 billion in potentially preventable
health care expenditures annually. Alarmingly, successful treatment of G- infections has become more and more
challenging, primarily due to the rapid emergence of multidrug-resistance (MDR) to existing and even newly
approved antimicrobial agents in these pathogens. The World Health Organization (WHO) and the US Centers
for Disease Control and Prevention (CDC) published their lists of priority pathogens and antibiotic resistance
classification in 2017 and 2019, respectively, in which carbapenem-resistant Acinetobacter baumannii (CRAB),
carbapenem-resistant Enterobacteriaceae (CRE), and MDR or carbapenem-resistant Pseudomonas aeruginosa
(CRPA) are among those of the biggest concern, highlighting the urgent need for discovery and developing novel
antibacterial agents for MDR G- infections. To address this need, we have created a new class of antibiotics,
the biamyxins (BMX), which are semisynthetic, dimeric polycationic peptides that tightly bind lipopolysaccharide
(LPS) in the outer membrane of G- pathogens including CRAB, CRPA, and CRE isolates, thus confer the broad-
spectrum G- coverage with potent antimicrobial activity. BMXs are constructed from two identical semisynthetic
polymyxin-derived compounds joined by a central linker. Unlike monomeric polymyxins or recent derivatives, we
designed novel dimeric peptide-like compounds optimized to bind the LPS of both sensitive and COL-resistant
(COL-R) G- pathogens using cooperative binding. This innovative approach engages modern medicinal
chemistry guided structural design to maximize potency while minimizing toxicity of BMX molecules. HCC-0010
is our current lead compound and has demonstrated highly promising properties as a therapeutic agent: broad
spectrum antibacterial activity, low cytotoxicity, acute safety in rodents, in vivo efficacy in mouse models of
septicemia and pneumonia due to multiple G- species including A. baumannii, P. aeruginosa, and K.
pneumoniae, and a favorable plasma half-life (~5 hours) and efficient target tissue (lung and epithelial lining
fluid) distribution in mice. Further optimization of potency and spectrum and in-depth evaluation of
pharmacological and toxicological properties of this lead are proposed in this application. The overarching goal
of this proposal is to identify a qualified lead development candidate by Year 4 and pursue an Investigational
new drug (IND) candidate through Years 4 and 5, that meets these criteria: 1) acceptable stability, tolerability
and physiochemical properties for IV formulation, 2) MIC90s ≤2 µM against clinical isolates (including MDR) of
Klebsiella, Acinetobacter, Pseudomonas and E. coli, 3) MIC90s ≤4 µM ag...

## Key facts

- **NIH application ID:** 10859228
- **Project number:** 1R01AI182297-01
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Yanan Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $802,798
- **Award type:** 1
- **Project period:** 2024-07-02 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10859228

## Citation

> US National Institutes of Health, RePORTER application 10859228, Novel Biamyxins targeting multidrug resistant Gram-negative bacterial infections (1R01AI182297-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10859228. Licensed CC0.

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