Malaria Parasite's Resistance to Prophylactic Drug Tied to Mutations in GCH1 Gene

By David Douglas

January 13, 2021

NEW YORK (Reuters Health) - Growing resistance of the malaria parasite Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) appears to be linked to new mutations of the GCH1 gene, findings that could help guide countermeasures, according to researchers in the U.K.

"SP was widely used across the world as an alternative to chloroquine when that drug was threatened by parasite resistance. The efficacy of SP for treating malaria patients also fell quite quickly due to resistance, but it retained good effectiveness as a preventative drug rather than a therapy for ill patients," explained Dr. Taane G. Clark of The London School of Hygiene and Tropical Medicine.

Thus, it has "been retained for 'intermittent preventative treatment' (IPT) in people at particular risk of malaria infection," he told Reuters Health by email. "Millions of pregnant women and children under 5 living under significant malaria threat are currently being protected by IPT with SP alone or in combination with other drugs, and this is due to be extended to infants (IPTi) under current World Health Organization (WHO) plans."

In a paper in PLOS Genetics, Dr. Clark and colleagues note that SP resistance is caused by mutations in the P. falciparum parasite dihydrofolate reductase gene (pfdhfr), the dihydropteroate synthase gene (pfdhps) and recently novel structural variants in and around the GTP cyclohydrolase 1 (pfgch1) gene have been described.

To investigate further, the team analyzed the whole-genome sequence data of more than 4,100 P. falciparum isolates from 29 malaria endemic countries. Across 1,171 (28.3%) of the samples they identified ten unique amplifications in the pfgch1 gene or promoter regions. These were seen in 23% of Southeast Asian isolates and 34% of those from Africa.

The selection of P. falciparum with pfgch1 amplifications, write the researchers, "may enhance the fitness of parasites with pfdhfr and pfdhps substitutions, potentially threatening the efficacy of this regimen for prevention of malaria in vulnerable groups."

Coauthor Dr. Colin J. Sutherland added in an email to Reuters Health, "The growth in the number of malaria parasites with GCH1 locus mutations is concerning, because the mutations enhance resistance to SP and may encourage the evolution of new resistant strains."

"Resistant parasites are adapting to become fitter in some way linked to the GCH1 locus," he said. "We need to understand how GCH1 mutations work and monitor them as part of malaria surveillance programs, especially in vulnerable groups such as children and pregnant women."

Dr. Abdoulaye Djimde of the University of Science, Techniques and Technologies of Bamako, in Mali, who was not involved in the research, told Reuters Health by email that the paper "is an excellent example of the value of secondary analyses of publically available malaria parasite genetics data. Their findings shed more light on P. falciparum genetic diversity in sub-Saharan Africa and its potential impact on the evolution of antimalarial drug resistance."

Dr. Djimde, who is chief of the Molecular Epidemiology and Drug Resistance Unit, added, "At its current state I see the most value of these findings in calling for laboratory studies to improve our understanding on the biological mechanisms involved in P. falciparum resistance to sulfadoxine and/or pyrimethamine. I am not convinced on the potential added value of typing pfgch1 polymorphisms as a new tool for molecular surveillance of SP resistance in the field. Indeed, these polymorphisms appear to be related to improving the fitness of resistant parasites rather than to drug resistance itself."

SOURCE: PLOS Genetics, online December 31, 2020.