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Synergistic action between peptide-neomycin conjugates and polymyxin B against multidrug-resistant gram-negative
Sandra Story1, Liuwei Jiang2, Alain S Leutou1
1NUBAD, LLC, Greenville, SC, United States.
Frontiers in Microbiology
|August 25, 2025
Summary
Novel peptide-neomycin conjugates show synergy with polymyxin B against drug-resistant bacteria. This combination circumvents aminoglycoside-modifying enzymes, offering a promising strategy for developing new antimicrobial therapies.
Area of Science:
- Microbiology
- Drug Discovery
- Antimicrobial Resistance
Background:
- Antimicrobial resistance is a growing global health threat, with drug-resistant bacterial infections predicted to cause 10 million deaths annually by 2050.
- Novel antibacterial agents have not been developed in 30 years, increasing interest in combination therapies using existing drugs.
- Aminoglycosides and colistin are often combined to treat multidrug-resistant bacterial pneumonia.
Purpose of the Study:
- To investigate the synergistic antibacterial activity of a peptide-neomycin library combined with polymyxin B against extensively drug-resistant and pandrug-resistant bacteria.
- To evaluate the efficacy of peptide-neomycin conjugates designed to evade aminoglycoside-modifying enzymes.
- To assess the development of resistance to these combinations.
Main Methods:
- Screening of neomycin-susceptible and resistant strains of *Acinetobacter baumannii*, *Klebsiella pneumoniae*, and *Pseudomonas aeruginosa* for synergy with polymyxin B.
- Utilizing two-way checkerboard and time-kill assays to determine synergistic effects.
- Testing peptide-neomycin conjugates containing cysteine, arginine, or tryptophan against resistant bacterial strains.
Main Results:
- Neomycin alone or with other aminoglycosides showed additive to indifferent activity with polymyxin B.
- Several peptide-neomycin conjugates (with cysteine, arginine, or tryptophan) demonstrated synergy with polymyxin B, reducing minimal inhibitory concentrations by 8-64-fold for the conjugate and 2-8-fold for polymyxin B.
- These synergistic combinations were most effective against *A. baumannii* and *K. pneumoniae* with 16S rRNA methyltransferase genes and pandrug-resistant *P. aeruginosa*.
- No resistance developed to the R-, C-, or RC-NEO conjugates and polymyxin B combination over 14 days in susceptible strains.
Conclusions:
- Peptide-neomycin conjugates can overcome aminoglycoside-modifying enzymes, a key mechanism of bacterial resistance.
- The combination of specific peptide-neomycin conjugates and polymyxin B shows significant synergistic activity against challenging multidrug-resistant bacteria.
- This approach represents a promising strategy for the development of novel peptide aminoglycoside-based antimicrobial drugs.
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