Part 1 linked here: https://eeganra5527.medium.com/the-deadliest-lifesavers-part-1-bacteriophages-in-medicine-f94f4c732175
Bacteriophage therapy is the best solution to fighting antibiotic resistance. However, we cannot harness the abilities of phage therapy without first solving the issues that come with it.
The Problems:
It is possible, or even certain, that the bacteria evolve resistance to the phages used. Even with phage cocktails, there is still a chance that the bacteria evolve resistance with a multitude of methods, from changing their receptors to using CRISPR.
On top of that, not all phages are actually suitable for medical use. Some phages can use the lysogenic cycle instead of the lytic cycle, which means that they won’t actually be able to kill a bacterium as easily as lytic cycle phages. Other phages might be hard to keep stable in normal temperatures and environments or could produce toxins and other unwanted side effects.
While the phages might not directly harm the human body, the immune system might recognize the phages as a pathogen and proceed to wipe them out, which won’t help the bacterial infection.
Some phages simply might have a low virulence, meaning that they aren’t as good at infecting and killing bacteria as phages with higher virulence. Because of this, they might be needed in higher doses in order to effectively stop infection or let the bacteria evolve resistance faster.
Phages also infect a very small range of hosts. Usually, phages can only infect a few closely related species or strains of a species, and rarely more than that. Bacteria can evolve into new strains, and because the phages are so specific, they won’t be able to effectively infect the bacterium. And while phage cocktails exist, they are expensive and hard to produce.
The Solutions
Phage resistance in bacteria is arguably the main concern in phage therapy. Luckily, there are multiple possible solutions to the problem, beginning with phage-antibiotic combinations.
Combinations of phages and antibiotics, known as phage-antibiotic synergy, offer potential because the mechanisms of bacterial resistance to antibiotics are very different from the resistance methods to phage therapy. The whole idea has been studied by scientists, and the results come in a wide range. Some phage-antibiotic combinations have a positive effect on each other, others have a negative effect, and certain combinations are simply neutral.
There are multiple ways to use the positive effects of phage-antibiotic synergy. A curious example occurred in a multi-drug-resistant Pseudomonas aeruginosa culture. The P. aeruginosa bacteria had efflux pumps, which were pumps that literally pumped antibiotics out of the bacterial cells so that they do less harm. Researchers used a phage that targets a specific part of the efflux systems in those bacteria.
When the phages were used, the bacteria evolved resistance by changing the proteins on the efflux pumps. The phages lost their virulence against the bacteria, but the efflux pumps became less efficient at removing the antibiotics, which made the bacteria more susceptible to the antibiotics.
The whole idea of making “one or the other” situations could become a very helpful method of killing resistant bacteria and is one of the ways that phage antibiotic synergy works.
But what of the other problems, like harmful toxins or low virulence? They may all be solved by a weapon used against them: CRISPR.
CRISPR, or more formally CRISPR-Cas9, is an immune defense that was found in bacteria that protects it from genetic attacks, such as those from phages.
When a bacterium gets infected by a phage and survives, then the CRISPR system starts. The CRISPR molecule would “remember” a certain snippet of the genetic code of the invading phage, so when the phage infects it again, it would recognize it. Then, Cas-9 would “cut” the nucleic code and destroy the virus’s genome, stopping it from successfully infecting the bacterium.
However, CRISPR can also be used for gene editing. This process works similarly to the original system in that it cuts DNA in specific places. The CRISPR system used for gene editing allows for a new gene, chosen by the user, to be placed where the original was cut, allowing scientists to change the genomes of living things easily.
By using CRISPR, scientists can edit the genomes of phages, allowing them to change certain characteristics of them, from increasing virulence to widening the target range.
For example, if a phage produces harmful toxins, scientists can use CRISPR to knock out the genes that code for those toxins, allowing the phage to be safer for human use.
With CRISPR technology, scientists are given a way to advance evolution. Instead of making random mutations like evolution, scientists can control which parts get changed and in what way. While is it complicated for scientists to make so many changes, it could allow them to solve many of the problems with phages.
Furthermore, phages come with many neat side effects. For example, bacteriophages require low dosage cycles. This means that in some situations, one dose of phages is enough to cure the disease, as the phages will increase if there are more bacteria to kill.
Conclusion
As it stands today, we cannot successfully use the amazing and admirable abilities of bacteriophages without the necessary research or permits. Research in phage therapy has been eclipsed by the discovery of chemical antibiotics. Phage therapy is widely used only in a very small number of countries and is almost never used anywhere else.
Fortunately, phage therapy is on the rise. Studies are now being conducted and there is even a scientific journal dedicated to the research of phages, aptly named Bacteriophage.
It is necessary that we must endorse this new cure if we are to keep bacterial infections low, and many are beginning to understand this. As long as humanity continues to grow its research in bacteriophage therapy, it is certain that the deadliest lifesaver can protect humanity from bacterial infections.
