Mutational fitness landscape and resistance

• Published in: Current opinion in structural biology 2023-01, Vol.78, p.102525-102525
• Main Authors: Flynn, Julia, Samant, Neha, Schneider-Nachum, Gily, Tenzin, Tsepal, Bolon, Daniel N.A.
• Format: Article
• Language: English
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2022.102525

Robust technology has been developed to systematically quantify fitness landscapes that provide critical opportunities to improve our understanding of drug resistance and define new avenues to develop drugs with reduced resistance susceptibility. We outline the critical importance of drug resistance studies and the potential for fitness landscape approaches to contribute to this effort. We describe the major technical advancements in mutational scanning, which is the primary approach used to quantify protein fitness landscapes. There are a number of complex steps to consider in planning and executing mutational scanning projects including developing a selection scheme, generating mutant libraries, tracking the frequency of variants using next-generation sequencing, and processing and interpreting the data. Key experimental parameters impacting each of these steps are discussed to provide to aid in planning fitness landscape studies. There is a strong need for improved understanding of drug resistance, and fitness landscapes provide a promising new approach.