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A Synthetic Phage-Peptide Conjugate as a Potent Antibacterial Agent for Pseudomonas aeruginosa Infections
Yanxi Yang1,2, Shelby Vexler1,2, Maria C Jordan3
1Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, United States.
Abstract:
Antibiotic resistance among Gram-negative organisms is a major challenge. Some molecules, including antimicrobial peptides such as polymyxin B (PMB), are antibacterial but toxic due to low specificity, causing poor clinical utility. Drug delivery to bacterial cells using a biocompatible nanomaterial is a possible approach to securing such drugs. We engineered a nonlytic phage to recognize the lipopolysaccharide of Gram-negative bacteria and cross-linked thousands of peptides per virion, making "PMB-M13αLPS". PMB-M13αLPS reduced the minimum inhibitory concentration in vitro by ∼2 orders of magnitude across multiple pathogen strains. Immunocompetent mice with multidrug-resistant P. aeruginosa pneumonia or corneal infection were effectively treated by PMB-M13αLPS, which showed potency ∼2 orders of magnitude greater in vivo compared to that of PMB. PMB-M13αLPS was well-tolerated, with no toxic effects. Conjugates of antimicrobial peptides and synthetic phages combine engineerable targeting with large payload capacity, improving potency and therapeutic index for otherwise toxic molecules.
Insights
Engineered phage nanoparticles carrying polymyxin B (PMB) effectively target Gram-negative bacteria. This novel drug delivery system significantly enhances antibiotic potency and reduces toxicity for treating resistant infections.
Area of Science:
- Biotechnology
- Nanomedicine
- Microbiology
Background:
- Antibiotic resistance in Gram-negative bacteria poses a significant global health threat.
- Antimicrobial peptides like polymyxin B (PMB) show antibacterial activity but have limited clinical use due to toxicity and low specificity.
- Nanomaterial-based drug delivery offers a strategy to improve the therapeutic index of toxic antimicrobial agents.
Purpose of the Study:
- To engineer a phage-based nanoparticle for targeted delivery of polymyxin B (PMB) to Gram-negative bacteria.
- To evaluate the efficacy and safety of the engineered PMB-M13αLPS conjugate in vitro and in vivo.
Main Methods:
- Engineered a nonlytic phage (M13) to recognize Gram-negative bacterial lipopolysaccharide (LPS).
- Cross-linked thousands of PMB peptides onto each engineered phage virion, creating PMB-M13αLPS.
- Assessed the minimum inhibitory concentration (MIC) of PMB-M13αLPS against Gram-negative pathogens in vitro.
- Evaluated the therapeutic efficacy and toxicity of PMB-M13αLPS in immunocompetent mice with multidrug-resistant *P. aeruginosa* pneumonia and corneal infections.
Main Results:
- PMB-M13αLPS demonstrated a reduction in MIC by approximately two orders of magnitude against multiple Gram-negative pathogen strains.
- Effective treatment of multidrug-resistant *P. aeruginosa* infections in mice was achieved with PMB-M13αLPS.
- PMB-M13αLPS exhibited approximately two orders of magnitude greater potency in vivo compared to unconjugated PMB, with no observed toxic effects.
Conclusions:
- Conjugating antimicrobial peptides with engineered bacteriophages provides a viable strategy for targeted drug delivery.
- This approach significantly enhances the potency and therapeutic index of toxic antimicrobial molecules like PMB.
- PMB-M13αLPS represents a promising therapeutic candidate for combating antibiotic-resistant Gram-negative bacterial infections.
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