Viruses have long been maligned as worthless, pseudo-alive parasites, but treatment for antibiotic-resistant infections may be about to go viral. No, we don’t mean cats taking medicine on video (although…). No, this is phage therapy.
Phages are viruses that infect bacteria, and research into using them to treat bacterial infections goes back decades, especially in the former Soviet states. Phage therapy never made it very far in the West though; apparently the iron curtain had a sub-micron pore size.
But with antibiotics losing their punch, drug-resistant bacteria have aroused renewed interest in phages. Phages can be counter-evolved as bacteria develop resistance, and their specificity means they won’t cluster-bomb the gut microbiome, like some antibiotics.
Two papers on the subject recently caught our eyes for their novel approaches. One used non-replicating “phagemids” to avoid safety issues, and the other aimed to remove resistance genes from resident hospital bacteria.
Phagemids for Safer Phage Therapy
One of the main concerns with phage therapy is safety. For one thing, the idea of releasing self-replicating viruses into a patient can make people queasy. For another, when phages lyse bacteria, they release endotoxins that can cause collateral damage.
To get around the replication issue, Russell Krom in Jim Collins’ lab in Boston used a two-plasmid helper system to produce phages. The first helper plasmid expresses all the necessary phage genes, while the second payload plasmid gets packaged into the phage. Since the payload plasmid doesn’t have the phage genes, it can’t produce more phages in the wild. As a second bonus, eliminating phage genes from the payload also avoided superinfection exclusion, in which virus-infected bacteria are resistant to repeated infection.
To avoid lysing targeted bacteria, the researchers found toxin genes that would kill infected cells without lysing them. In mice, the phagemid system successfully treated peritonitis, and in vitro, it was much better than phages at avoiding bacterial resistance.
Phage to Purge Resistance Genes from Hospitals
In a completely different approach, Ido Yosef and Miriam Manor in Udi Qimron’s lab aimed to treat the hospital instead of the patient. Many hospital infections come from bacteria that escape cleaning and then make their way into vulnerable patients. Because hospitals use antibiotics so often, their residential microbes have been selected for antibiotic resistance.
Phage therapy could eliminate resistance genes by delivering CRISPR cassettes that target those genes, but combining this with antibiotics will always promote “escape” mutants that remain resistant. To avoid this, these researchers propose a two-step method.
First, lysogenic (genomically integrating) phages would deliver a CRISPR cassette targeting resistance genes. Next, antibiotic-sensitive bacteria would be selected by infecting with lytic (killer) phages with the same short sequence targeted by the CRISPR payload. CRISPR would chop up resistance genes (and the lytic phage) in lysogenized bacteria, while non-lysogenized bacteria would be killed by the lytic phage.
The idea here is that it’s impossible to eliminate all bacteria from hospitals, so we may as well make them antibiotic-susceptible. Then when infections do occur, they can easily be treated. Similar to how a healthy gut microbiome can prevent bad bacteria from taking over, maybe we can make the hospital microbiome “healthy”, or at least less threatening.
The authors envision this targeted selection step being used in sprays and hand soaps alongside traditional disinfection and cleaning. The idea is definitely cool, but if bad bacteria somehow escape normal cleaning, it’s not clear if the combo-phage spray would get to them any better. We’ll keep a spare spray can around just in case.
Let’s help these papers go viral! Here are the links: