January 2020

Pseudomonas aeruginosa is a killer. This bacterium causes thousands of deaths each year in the United States and was recently placed on the World Health Organization’s list of 12 antibiotic resistant pathogens that pose the most serious threats to human health. P. aeruginosa tends to hit people when they are down — already in the hospital recovering from some other injury or disease. In this setting, the bacterium is exposed to many different drugs, encouraging the evolution of antibiotic resistance. There, it also encounters many different bacteria, allowing the microbe to acquire from these other lineages bits of DNA that contain genes for resistance to still other antiobiotics. The result is deadly pathogen that is extremely difficult to fight. But scientists have not given up hope. Now, new research suggests that we may be able to exploit the bacterium’s own evolutionary tendencies to beat it.

Where's the evolution?

The new research focuses on evolutionary trade-offs. An evolutionary trade-off occurs when evolving increased performance in one area means simultaneously evolving decreased performance in another. For example, growing sharp thorns helps protect plants from being eaten but also takes a lot of energy that could otherwise be used to produce seeds. So a plant that evolves thorns simultaneously evolves to have less energy available for reproduction. In everyday life, we often make trade-offs by conscious decision (e.g., “I’m going to wear mittens so my hands will be warmer, even though I won’t be able to text”), but in evolution, trade-offs are not a choice at all. Natural selection simply pushes a lineage towards whichever end of the trade-off confers greater survival and reproductive success in the current environment, regardless of what individual organisms might choose, prefer, or try to do.

In the case of P. aeruginosa, their trade-off occurs in a phenomenon known as collateral sensitivity. This means that when a bacterial lineage evolves resistance to one drug, it is also likely to evolve more vulnerability to a different drug. So increased performance against Drug A means decreased performance against Drug B. Collateral sensitivity occurs in many pathogens and also in diseases like cancer, where the cancerous cell lineage may evolve resistance to certain drugs, while evolving increased sensitivity to others.

Collateral sensitivity then is an opportunity for medical treatment. Imagine if we could treat a patient with Drug A, knowing that at the same time the bacterium was evolving resistance to Drug A, it was also becoming increasingly sensitive to Drug B. Then if we gave the patient a large dose of Drug B, we might be able to wipe out the infection completely! However, the attempt could also backfire: What if the bacterium simply evolved resistance to Drug A and maintained its resistance to Drug B? We’d have caused the evolution of a multi-drug resistant bacterial strain that is extremely difficult to treat and could go on to infect others.

Before trying such a risky treatment, medical researchers would need to know more. How predictable is the evolution of collateral sensitivity in this pathogen? Does it happen reliably? Is the strategy likely to backfire, or succeed and wipe out the bacteria? What drug combinations are most effective? Recent research attempted to answer those questions for P. aeruginosa.

The scientists leading that study tried out different doses and combinations of drugs on different bacterial lineages using carefully controlled experiments. Because bacteria reproduce so quickly, biologists can easily observe evolution in the lab across hundreds of bacterial generations. And because bacteria are so small, biologists can test the same experimental set-up over and over again to find out if the bacteria always evolve in the same ways and what factors tip their evolution in a particular direction.

The experiments provided some guidance for using collateral sensitivity to our advantage. The study found that a population or lineage of P. aeruginosa was most likely to be wiped out when it was first exposed to an antibiotic that blocks the bacterium’s ability to build proteins and allowed to evolve resistance to this drug, and then got additional treatment with a strong dose of a second antibiotic that prevents the bacterium from building its cell wall. The bacteria were particularly sensitive to this second antibiotic in this situation… or at least they were in a petri dish. Lab experiments like these will lay the foundation for future studies that determine whether this is a viable treatment option for real patients in the messy, uncontrolled world outside the lab.