CAPTURE - Combating Pseudomonas aeruginosa infections with antimicrobial peptide carriers
The bacterium Pseudomonas aeruginosa is a leading cause of hospital-acquired infections, including ventilator-associated pneumonia and sepsis [1]. This pathogen exacerbates the condition of already compromised patients and exhibits high resistance to antibiotics, posing a significant challenge in healthcare settings [2]. Our project aims to combat P. aeruginosa through a novel approach involving carriers for Antimicrobial Peptides .
The aim is to ensure the effective delivery of AMPs directly into the bacterial cells, thereby maximizing their antimicrobial activity. By encapsulating a plasmid encoding a potent AMP within specialized carriers, we strive to create a targeted therapeutic system capable of eradicating P. aeruginosa infections. The carriers will be administered via an aerosol delivery system, enabling targeting of bacterial infections in the lungs. To validate our approach we will initially test the system using the strain Pseudomonas fluorescens as a model organism. This cutting-edge research holds promise for developing effective treatments against P. aeruginosa infections, potentially improving patient outcomes.
Pseudomonas aeruginosa Infections: A Significant Challenge
Pseudomonas aeruginosa presents a significant challenge in modern healthcare due to its intrinsic resistance to antibiotics and its remarkable ability to acquire new resistance mechanisms. This opportunistic pathogen is a leading cause of severe healthcare-associated infections, particularly in immunocompromised individuals and those in intensive care units. Its ability to form biofilms on medical devices and tissues further complicates treatment, leading to persistent infections that are difficult to eradicate. The high morbidity and mortality rates, combined with the substantial economic burden on healthcare systems, underscore the urgency of addressing this issue.
P. aeruginosa is associated with 559,000 annual deaths globally [3]. P. aeruginosa produces beta-lactamases, rendering most penicillins and cephalosporins ineffective [4]. Current therapies rely on inhaling colistin or tobramycin, chosen based on the patient’s condition, and sometimes combined with ceftazidime for increased potency. Yet, even these measures can only provide temporary respite, curing early infections after weeks of treatment but failing to eradicate chronic cases.
Developing new antimicrobial agents, innovative therapies, and advanced treatment modalities is not just a necessity – it’s an imperative. By leveraging cutting-edge research and technology, we developed CAPTURE as a formidable strategy to combat P. aeruginosa infections. Our goal is to harness a targeted approach, eliminating the bacteria while minimizing side effects, sparing patients’ already compromised lungs from the onslaught of a highly effective yet indiscriminate antibiotic cocktail.
With CAPTURE, our goal is to find a better solution against the threat of P. aeruginosa infections and provide new hope for patients suffering from these difficult-to-treat infections.
How can we overcome the antibiotics resistance in Pseudomonas?
To combat antibiotic resistance in Pseudomonas aeruginosa, our approach employs a multi-pronged strategy. First, we harness the power of antimicrobial peptides (AMPs), which are evolutionarily conserved components of immune systems [5]. Unlike conventional antibiotics that inhibit metabolic processes, AMPs disrupt bacterial cell membranes through their cationic properties, making it difficult for bacteria to develop resistance [6,7]. Instead of delivering pre-synthesized AMPs, we opt for a plasmid encoding a potent AMP, placing its expression under the control of a constitutively active, Pseudomonas-specific promoter. This strategy ensures high levels of peptide synthesis within the target bacteria, circumventing the need for expensive external synthesis and purification processes.
To efficiently deliver this plasmid, we employ two distinct delivery systems: liposomes and outer membrane vesicles (OMVs). Liposomes, vesicular structures formed by phospholipids, have been extensively researched and adapted for drug and gene delivery applications, including the COVID-19 mRNA vaccines [8]. Their properties, such as lipid composition, size, and surface modifications, can be tailored to enhance encapsulation, stability, and target specificity [9].
OMVs, on the other hand, are naturally secreted by gram-negative bacteria and play crucial roles in horizontal gene transfer and stress responses [10]. By engineering an Escherichia coli strain devoid of common outer membrane proteins, we produce “clean” OMVs that primarily display our membrane protein of interest [11]. This setup ensures minimal immune response and maximal surface expression of targeting ligands. Through the SpyCatcher/SpyTag system [12], we can fuse phage tail proteins specific to P. aeruginosa [13], enabling selective targeting and binding to the pathogen. Our modular approach allows for the incorporation of multiple phage tail proteins, offering versatility and the potential for broad-spectrum antibacterial therapies.
References
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