Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs

• DOI: 10.7554/elife.94144.3
• Publication Date: 2024-09-10T16:45:55Z
• Authors: Kara Schmidlin; Sam Apodaca; Daphne Newell; Alexander Sastokas; Grant Kinsler; Kerry Geiler-Same...
• Keywords: Leverage (statistics); Genetic Fitness

There is growing interest in designing multidrug therapies that leverage tradeoffs to combat resistance. Tradeoffs are common evolution and occur when, for example, resistance one drug results sensitivity another. Major questions remain about the extent which reliable, specifically, whether mutants provide a given all suffer similar tradeoffs. This question difficult because drug-resistant observed clinic, even those evolved controlled laboratory settings, often biased towards large fitness benefits. Thus, mutations (and mechanisms) may be more diverse than current data suggests. Here, we perform experiments utilizing lineage-tracking capture fuller spectrum of give yeast cells advantage fluconazole, antifungal drug. We then quantify each 774 across 12 environments, finding these group into classes with characteristically different Their unique imply affects through underlying mechanisms. Some groupings find surprising. For some resist single drugs do not their combination, while others do. And same gene have others. These findings, on hand, demonstrate difficulty relying consistent or intuitive when treatments. On other by demonstrating hundreds adaptive can reduced few groups characteristic tradeoffs, our findings yet empower strategies More generally speaking, grouping likely affect mechanisms, work guides efforts map phenotypic effects mutation.