A team of CWRU researchers penned an article titled “Fitness Seascapes are Necessary for Realistic Modeling of the Evolutionary Response to Drug Therapy,” which was recently published in Science Advances.
Led by Eshan King, a student in the Medical Scientist Training Program at the School of Medicine, the research team also included:
- Davis Weaver (GRS ’23, systems biology and bioinformatics), an MD candidate,
- Anna Stacy (CWR ’25), a recent graduate who studied physics and pre-medicine; and
- Jacob Scott, professor at the School of Medicine and associate director for data sciences at the Case Comprehensive Cancer Center.
Using an empirical fitness seascape of E. coli with combinations of four drug resistance mutations, the team integrated data into pharmacokinetic-pharmacodynamic (PK-PD) simulations. In this study, they found that a higher mutation supply increases resistance risk and that early adherence—especially the second dose—is crucial for preventing resistance. This marks the first use of an empirical fitness seascape in computational PK-PD studies, offering new insights into antibiotic resistance.
About the study
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling of host-pathogen interactions has enhanced an understanding of drug resistance. However, how combinations of drug resistance mutations impact dose-response curves remain under appreciated in PK-PD studies. The fitness seascape model addresses this by extending the fitness landscape model to map genotypes and dose-response functions, which enables the study of evolution under fluctuating drug concentrations.