Recent advancements in synthetic biology have opened new avenues for addressing antimicrobial resistance (AMR), a pressing global health threat. Synthetic biology encompasses the design and engineering of new or modified living systems to combat drug-resistant bacteria effectively. This field promises innovative therapies, including phage therapy and engineered probiotics, which offer targeted alternatives to traditional antibiotics. These methodologies are gaining recognition as viable solutions to overcome the limitations posed by conventional antimicrobial treatments.
Antibiotic resistance presents a significant challenge to public health, contributing to approximately 1.27 million deaths worldwide in 2019 alone. The crisis is exacerbated by the overuse and inappropriate prescribing of antibiotics, coupled with the stagnation in the development of new antimicrobial drugs. Major pharmaceutical companies are increasingly abandoning the field of antibiotic development due to high costs, stringent regulatory requirements, and the inevitable emergence of resistance in newly developed drugs. This has intensified the urgency for alternative solutions that can be tailored specifically to target drug-resistant bacterial infections.
Synthetic Biology’s Role in Combating AMR
Synthetic biology has emerged as a crucial player in the development of new antimicrobial agents, offering advanced techniques to enhance the efficacy and specificity of antimicrobials. Researchers are actively exploring various methods to improve existing antibiotics and design phages with specific targeting capabilities. This involves modifying existing antibiotics for better performance, engineering more efficient production methods, and creating phages tailored to target specific bacterial strains, thus ensuring a more effective approach to combating AMR.
Phage therapy, which utilizes bacteriophages to target and kill specific bacterial strains, is experiencing a renaissance due to its specificity and minimal impact on gut microbiota. Although phages were discovered over a century ago, their use declined with the advent of antibiotics in the West. However, the rise of AMR has rekindled interest in phages as viable antimicrobial agents. Phages offer the advantage of targeting bacteria without harming beneficial microbiota, making them a promising alternative to conventional antibiotics in managing drug-resistant bacterial infections.
Natural phages face limitations such as a restricted host range and potential for phage resistance, which can hinder their effectiveness. Synthetic biology techniques can address these challenges by engineering phages with enhanced therapeutic capabilities. Methods like recombineering, CRISPR-Cas-assisted selection, and synthetic genome assembly allow precise modifications of phage genomes, leading to the development of phages that can specifically target and eliminate drug-resistant bacteria. This approach not only enhances the therapeutic potential of phages but also provides a sustainable solution to the problem of antimicrobial resistance.
Clinical Trials and Regulatory Hurdles
Despite the potential of phage therapies, they have yet to receive FDA approval for clinical use in the United States. Researchers and clinicians must submit investigational new drug applications to administer phages, a process that underscores the regulatory hurdles faced by these innovative therapies. Ongoing clinical trials aim to provide robust evidence supporting the efficacy of phage therapy. For instance, a notable clinical trial is investigating the use of phage therapy for adults with cystic fibrosis harboring Pseudomonas aeruginosa in their lungs. Such trials are critical for establishing the clinical efficacy and safety of phage-based treatments.
One notable example of synthetic biology enhancing phage therapy is SNIPR Biome’s engineering of phages armed with CRISPR-Cas machinery to specifically target E. coli, a common cause of bloodstream infections. By leveraging synthetic biology, the team developed SNIPR001, a combination of four phages that target various E. coli strains. This product has entered clinical development, exemplifying the fusion of natural phage abilities with synthetic enhancements to combat multi-resistant bacteria more effectively. This approach highlights the potential of synthetic biology in transforming phage therapy into a precise and reliable treatment for drug-resistant infections.
However, extensive clinical trials are essential to ensure the safety and efficacy of these therapies. Regulatory bodies require comprehensive data demonstrating the effectiveness and safety of phage therapies before granting approval for widespread clinical use. The complexity and cost of these trials pose significant challenges, but the potential benefits of phage therapy warrant continued investment and research. As more clinical evidence emerges, it is hoped that regulatory barriers will be overcome, paving the way for the broad adoption of phage therapies in clinical practice.
Enhancing Phages with Synthetic Biology
The advancement of synthetic biology has enabled researchers to enhance the capabilities of natural phages, addressing limitations such as restricted host range and phage resistance. Techniques like recombineering, CRISPR-Cas-assisted selection, and synthetic genome assembly have allowed precise modifications of phage genomes. This has led to the development of engineered phages with enhanced therapeutic capabilities. For instance, SNIPR Biome has engineered phages armed with CRISPR-Cas machinery to specifically target E. coli, a common cause of bloodstream infections. This product, SNIPR001, represents a combination of four phages targeting various E. coli strains and has entered clinical development.
Another promising approach in the field of synthetic biology is the engineering of probiotics for antimicrobial activity. Probiotics, often referred to as “beneficial” bacteria, can be programmed to recognize specific pathogens and secrete antimicrobials that disrupt harmful bacteria. Researchers at Gyeongsang National University have developed genetically modified probiotics capable of detecting and eradicating P. aeruginosa. They achieved this by creating a plasmid-based system that synthesizes P. aeruginosa-selective antimicrobial peptides (AMPs), and then transferred this system into the probiotic E. coli Nissle 1917. Preliminary results indicate that these engineered probiotics effectively inhibit P. aeruginosa in vitro and reduce its levels in mouse models of intestinal colonization, offering a promising alternative to traditional antibiotics.
However, further research is needed to verify the safety and efficacy of these probiotics in human subjects. The potential for the antimicrobials produced by these engineered probiotics to disrupt the gut microbiota or cause other adverse effects must be thoroughly investigated. Ensuring the safety and regulatory approval of these innovative therapies will be crucial for their successful implementation in clinical practice. As research progresses, the combination of synthetic biology and probiotics holds great promise for developing targeted and effective treatments against drug-resistant bacterial infections.
Engineering Probiotics for Antimicrobial Activity
Engineered probiotics represent another promising avenue in the fight against antimicrobial resistance. These “beneficial” bacteria can be programmed to recognize specific pathogens and secrete antimicrobials that disrupt harmful bacteria. One notable example is the work of researchers at Gyeongsang National University, who developed genetically modified probiotics capable of detecting and eradicating P. aeruginosa. They achieved this by creating a plasmid-based system that synthesizes P. aeruginosa-selective antimicrobial peptides (AMPs) and transferring this system into the probiotic E. coli Nissle 1917.
Preliminary results from this research are promising, indicating that these engineered probiotics effectively inhibit P. aeruginosa in vitro and reduce its levels in mouse models of intestinal colonization. However, further research is needed to verify the safety and efficacy of these probiotics in human subjects. The potential for the antimicrobials produced by these engineered probiotics to disrupt the gut microbiota or cause other adverse effects must be thoroughly investigated. Ensuring the safety and regulatory approval of these innovative therapies will be crucial for their successful implementation in clinical practice.
Quorum sensing, a communication process used by bacteria to coordinate behavior, has also been harnessed by synthetic biologists to develop microbial control systems. These systems can detect harmful pathogens before they spread, offering a preventative approach to microbial infections. Researchers at the University of Notre Dame have created a novel whole-cell biosensor to detect water contamination by P. aeruginosa and Burkholderia pseudomallei. This biosensor utilizes quorum-sensing signal systems to identify and respond to these pathogens, providing an early warning system for potential bacterial infections.
The integration of synthetic biology with precision medicine holds promise for developing targeted antimicrobial therapies with minimal impact on an individual’s microbiome. By leveraging genomic and artificial intelligence technologies, researchers can more accurately design phages and probiotics that target specific bacterial strains without disrupting beneficial microbiota. Future advancements might enable personalized antimicrobial treatments based on an individual’s microbiome data, enhancing treatment efficacy while reducing side effects.
Precision Medicine and Synthetic Biology
Despite the promise of phage therapy, it has not yet received FDA approval for clinical use in the United States. Researchers and healthcare providers must submit investigational new drug applications to administer phages, highlighting the regulatory challenges these treatments face. Ongoing clinical trials are crucial for demonstrating the effectiveness of phage therapy. One significant trial is examining phage therapy for adults with cystic fibrosis who have Pseudomonas aeruginosa in their lungs. Such studies are vital for proving the clinical safety and effectiveness of phage-based treatments.
A notable advancement in synthetic biology is SNIPR Biome’s engineering of phages equipped with CRISPR-Cas machinery to target E. coli, a common cause of bloodstream infections. This innovation led to the development of SNIPR001, a mix of four phages targeting different E. coli strains. Currently, in clinical development, SNIPR001 showcases the combination of natural phage properties with synthetic biology to better fight multi-resistant bacteria. This method exemplifies the potential of synthetic biology to make phage therapy a precise and dependable treatment for drug-resistant infections.
However, thorough clinical trials are essential to confirm the safety and effectiveness of these therapies. Regulatory authorities need extensive data to approve phage therapies for widespread clinical use. The complexity and expense of these trials are significant obstacles, yet the potential benefits of phage therapy justify ongoing investment and research. As more clinical evidence becomes available, it is hoped that regulatory challenges will be overcome, leading to the broader adoption of phage therapies in medical practice.
