Navigating the Fitness Landscapes of Plasmodium falciparum Dihydrofolate Reductase: Evolutionary Insights into Antifolate Resistance
Year: 2024
Type: preprint
Abstract: The rapid emergence of drug resistance in malaria parasites poses a significant challenge to the efficacy of antifolate treatments. Traditional drug development approaches, which often rely on empirical screening with limited mechanistic insights, tend to overlook the complex evolutionary mechanisms that enable Plasmodium falciparum to evade drug inhibition while preserving enzyme functionality. In this study, we employed computational techniques to investigate the mutational landscape of dihydrofolate reductase (DHFR), focusing on regions essential for enzyme stability and resistance. Our analysis uncovered conserved residues essential for stability, mutation hotspots that enhance adaptability under drug pressure and co-evolving clusters revealing critical functional interdependencies. Through integrated approaches including mutational scanning, epistatic interaction modeling, and fitness trajectory mapping, we elucidated distinct evolutionary pathways that drive resistance. We were able to track the adaptive paths taken by wild-type residues upon mutation, revealing the steps required to reach high-fitness peaks within the rugged fitness landscape. These findings provide valuable insights into the molecular mechanisms of antifolate resistance. We suggest that future drug design should target co-evolving networks and conserved regions to support the development of next-generation therapies to overcome resistance.
Authors: Danny Muzata, Dwipanjan Sanyal, A Shivram, Deeptanshu Pandey, Soumyananda Chakraborti, Aneesh S. Chivukula, Ravi Jasuja, Vladimir N. Uversky, Daniel Zielinski, Prajna D. Upadhyay, Mark Albers, Sourav Chowdhury
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4404050742