Team:NTNU Trondheim/Applied Design

Our Design

The core goal of our project is to develop a strategy that would solve the problem of bacterial resistance to antibiotics once and for all. Our reasoning goes like this: while small molecules used as antibiotics cannot be easily evolved to overcome bacterial resistance when it occurs, bacteriophage can very much be evolved. Thus phage-based treatments could tackle the issue of resistance by a constant evolution of the treatment agent (phage) in line with bacteria. The most intriguing case would be if one could evolve an anti-phage against a bacterium from a patient in a sufficiently short time to cure the patient with the new phage! We therefore made a chemostat-based evolution system that generates a diversity of phage, selecting them on their ability to infect phage-resistant bacteria, and made a biobrick that could increase their rate of mutation.

Phage versus Antibiotics

We used our chemostat system in different modes to first evolve a phage-resistant E.coli and then evolve a phage to kill it within 13 hours of evolution. (See the results section for further details). This showed that it is practical to perform fast phage evolution given a resistant bacterium. As compared to the rate of invention of new antibiotics this is of course a lot faster. However it is also easier for bacteria to evolve against phage than against antibiotics. A possible solution could be phage cocktails or pluripotent phage. The phage mix that we evolved, for example, was able to kill both the original bacterium and the one that was resistant to the original phage. In any case the system for allowing new phage into the market would have to be more dynamic than that of antibiotic approval. This means that the long times and huge amounts of money that are necessary to approve a new medicine would likely need to be abolished in the case of phage. This will not happen unless legislative changes are introduced.

However, as the prevalence of bacterial resistance to antibiotics increases, we think that more pressure will be put on the authorities to pursue such changes.

Environmental impact

There are already orders of magnitude more phage than bacteria in nature. The competition between bacteria and phage has lasted billions of years neither biological form being able to extinguish the other. It is therefore unlikely that we would manage to generate a phage to kill all bacteria in the lab given the time scales and the copy numbers that we are working with. It is likely that common pathogenic bacteria will evolve resistance against the phage used in treatment, but then we are back to the same issue that we successfully addressed in our project – we will always be able to evolve an antiphage.