Investigating the role of a non-synonymous mutation at dhfr codon 50 in maintaining sulphadoxine-pyrimethamine resistance in Plasmodium falciparum: a modelling study.
TL;DR
The study aimed to use empirical data and a mechanistic evolutionary model to explain the pre-discontinuation and post-discontinuation dynamics of SP-resistant P falciparum haplotypes, with a focus on the C50R mutation.
Abstract
Background
Resistance to antimalarials in Plasmodium falciparum leads to suboptimal treatment outcomes, leading to prolonged illness, complications, and increased mortality. Such resistance arises from mutations that increase parasite survival under drug pressure but typically reduce parasite growth because of metabolic costs. When drug pressure is sufficient (ie, owing to widespread treatment), these mutations can spread. It is commonly assumed that drug sensitivity returns once treatment is discontinued, as observed in the case of chloroquine resistance. However, this pattern has not been observed with sulphadoxine-pyrimethamine (SP) resistance. In South America, the 50R/51I/108N resistant type replaced the highly resistant 51I/108N/164L Pfdhfr variant. The study aimed to use empirical data and a mechanistic evolutionary model to explain the pre-discontinuation and post-discontinuation dynamics of SP-resistant P falciparum haplotypes, with a focus on the C50R mutation.
Methods
Using nine datasets on the prevalence of SP-resistant Pfdhfr mutations from Peru, together with published yeast expression data on antifolate sensitivity, the mechanism for the spread of the 51I/108N/164L and 50R/51I/108N mutants has been explained via a malaria-specific evolutionary genetic model.
Findings
The experimentally observed increase in parasite growth rate (metabolic advantage) associated with the C50R mutation explains the empirical patterns observed in Peru and is consistent with findings from other countries. Drug pressure is required for the emergence of the 50R/51I/108N mutant; however, it does not become dominant because other mutations confer higher levels of resistance. Once drug pressure is removed, the 50R/51I/108N mutant spreads and prevents the re-emergence of drug-sensitive types. In Iquitos, Peru, six years after SP discontinuation, when sensitivity was partly restored, the frequency of the 50R/51I/108N mutant increased from 3·77% to 62·5% within four years and reached fixation in the following year.
Interpretation
Our findings suggest that fitness-enhancing mutations should be considered when interpreting the emergence of novel resistance patterns; however, this hypothesis requires further empirical validation.
Funding
This work was funded by the Armed Forces Health Surveillance Division, the Global Emerging Infections Surveillance Branch, the German Academic Exchange Service (DAAD), the Saxon State Ministry of Science, Culture and Tourism (SMWK), and the Federal Ministry of Education and Research (BMBF).