Despite progress toward controlling malaria, it remains a leading cause of morbidity and mortality, particularly in Africa, where 95% of malaria deaths occur according to the World Health Organization. First-line drugs have repeatedly failed due to the spread of drug-resistant strains of Plasmodium falciparum, the parasite that causes malaria. Now, researchers at the University of California (UC), San Diego, report they have analyzed the genomes of hundreds of malaria parasites to determine which genetic variants are most likely to confer drug resistance.
The findings are published in Science in an article titled, “Systematic in vitro evolution in Plasmodium falciparum reveals key determinants of drug resistance,” and could help scientists predict antimalarial drug resistance and more effectively prioritize the most promising experimental treatments for further development.
“A lot of drug resistance research can only look at one chemical agent at a time, but what we’ve been able to do here is create a roadmap for understanding antimalarial drug resistance across more than a hundred different compounds,” explained Elizabeth Winzeler, PhD, a professor at UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and the Department of Pediatrics at UC San Diego School of Medicine. “These results will be useful for other diseases as well, because many of the resistant genes we studied are conserved across different species.”
The researchers analyzed the genomes of 724 malaria parasites evolved in the lab to resist one of 118 different antimalarial compounds, including established treatments and new experimental agents. By looking for patterns in the mutations that were associated with resistance, the researchers were able to identify unique features of these genetic variants, such as their physical location within genes, that could be used to predict which variations are likely to contribute to drug resistance.
“Through comprehensive analysis of the whole-genome sequences of 724 P. falciparum clones evolved to resist one of 118 small-molecule growth inhibitors, we identify previously unknown resistance alleles and genes, highlight drivers of multidrug resistance, and show that in vitro evolved variants are more likely to (i) be missense or frameshift, (ii) involve bulky amino acid changes, and (iii) occur in conserved, ordered protein domains,” the researchers noted. “Our data illustrate an evolutionary landscape in which each compound typically selects for driver mutations in only one or a few genes related to the compound’s mechanism of action, but multiple different mutations in a gene, ranging from substitutions near protein binding pockets to copy number amplification, can confer resistance.”
“The need for new, more effective malaria treatments is urgent, but funding for malaria research and drug development is very limited,” said Winzeler, who in addition to her role at UC San Diego is also the director of the Bill and Melinda Gates Foundation-funded Malaria Drug Accelerator. “However, the malaria research community is organized and highly collaborative, and our study was able to leverage these strengths to create a resource that will make the process of identifying and prioritizing new malaria treatments significantly easier.”
The researchers say their ultimate goal is to use machine learning to understand which compounds have the most risk of being compromised by resistance so that they can streamline the early drug development process and ultimately get treatments into clinical trials faster.
“The study also uncovers how networks of genes come together to mediate resistance across chemical classes, and provides a road map as we search for resistance-refractory compounds,” added David Fidock, PhD, co-author and a professor of microbiology and immunology at Columbia University Vagelos College of Physicians and Surgeons.
While the findings have significant implications for the development of new antimalarial drugs, the researchers also highlight that their approach could be relevant across different diseases. This is because the genetic machinery driving drug resistance is consistent across different pathogens and even within human cells. For example, many of the resistance-driving mutations identified in the study were from a protein in P. falciparum parasites, called PfMDR1, which can move substances between various parts of the cell, including transporting drugs away from their site of action. PfMDR1 has an exact counterpart in humans, and mutations in the human version are one of the key drivers of treatment resistance in cancer.
“The potential impact of this study is huge and extends well beyond a single disease,” said Winzeler. “Studying malaria gave us the opportunity to put this resource together, and we hope that these findings will help change the way we study drug resistance as a whole, not just in malaria.”
