3D rendering of yeast cells. Image credit: Ernesto Del Aguila III (CC0)
Mutations in an organism’s DNA make the individual more likely to survive and reproduce in its environment, passing on its mutations to the next generation. Mutations can alter the proteins that a gene codes for in many ways. This leads to a situation where seemingly similar mutations – such as two mutations in the same gene – can have different effects.
For example, two different mutations could affect the primary function of the encoded protein in the same way but have different side effects. One mutation might also cause the protein to interact with a new molecule or protein. Organisms possessing one or the other mutation will thus have similar odds of surviving and reproducing in some environments, but differences in environments where the new interaction is important.
In microorganisms, mutations can lead to drug resistance. If drug-resistant mutations have different side effects, it can be challenging to treat microbial infections, as drug-resistant pathogens are often treated with sequential drug strategies. These strategies rely on mutations that cause resistance to the first drug all having susceptibility to the second drug. But if similar seeming mutations can have diverse side effects, predictions about how they will respond to a second drug are more complicated.
To address this issue, Schmidlin, Apodaca et al. collected a diverse group of nearly a thousand mutant yeast strains that were resistant to a drug called fluconazole. Next, they asked to what extent the fitness – the ability to survive and reproduce – of these mutants responded similarly to environmental change. They used this information to cluster mutations into groups that likely have similar effects at the molecular level, finding at least six such groups with unique trade-offs across environments. For example, some groups resisted only low drug concentrations, and others were unique in that they resisted treatment with two single drugs but not their combination.
These diverse types of fluconazole-resistant yeast lineages highlight the challenges of designing a simple sequential drug treatment that targets all drug-resistant mutants. However, the results also suggest some predictability in how drug-resistant infections can evolve and be treated.
