The increase in microbial resistance to common antibiotics has led researchers to seek alternative means for treating infectious diseases. A recent study in Nano Letters by a team from MIT and Harvard has used a new strategy, termed “phagemids”, to target and kill specific pathogenic bacteria in a controlled manner.
Past research projects have looked into using bacteriophages as targeted therapies for pathogenic microbes that may be resistant to standard antibiotics. Bacteriophages only attack bacteria, and can be genetically engineered to only attack disease-causing microbes, leaving the host microbiome intact. Unfortunately, bacteriophages kill microbes by lysis, meaning the pathogen essentially explodes into the host intestine which can cause severe reactions from the immediate release of endotoxins.
New research, as shown by this paper, makes use of bacteriophage’s targeting abilities but prevents them from lysing the bacterial cell. Instead, the bacteriophage delivers a plasmid, a round or linear string of nucleotides coding for a few genes to dozens of genes that usually aids in bacterial survival fitness. In this instance, the plasmid codes for protein toxins and antimicrobial peptides that when produced by the targeted bacteria, disrupt survival from the inside, killing the microbe. Since the bacteriophage only inserts the toxin genes, and therefore cannot replicate within the cells, any eventual product is not considered a genetically modified organism, significantly increasing the likelihood of FDA approval.
One of the most important aspects of this work shows the lack of resistance obtained by the bacteria to the phagemids. Pathogenic microbes can eventually evolve to resist bacteriophage-mediated cell death (the lysis method). After treating multiple generations of bacteria with the phagemid method though, the researchers showed no strains developed resistance. These traits were also seen when the researchers tested their therapy in a mouse model of peritonitis infection: no resistance was observed, pathogenic microbial load was significantly reduced, and the therapy did not affect the mouse microbiome.
The researchers’ goal is to have clinics run a fast diagnostic test to identify the pathogen affecting a patient, then either give the patient a pre-made phagemid cocktail or have the clinical lab make a special one on the spot. Because there is no risk for resistance, a cocktail of various phagemid types could be given to patients with multiple or unidentified pathogens.
Edward Marks is a PhD student at the University of Delaware. His research involves the healing of myocardial tissue after major cardiac events using nanomedicine techniques, with the goal of pushing any advancement directly into the clinic. Edward received his BS from Rutgers University and Masters from the University of Delaware.