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Background  Malaria caused by zoonotic  Plasmodium knowlesi  is an emerging threat in Eastern Malaysia. Despite demonstrated vector competency, it is unknown whether human-to-human (H-H) transmission is occurring naturally. We sought evidence of drug selection pressure from the antimalarial sulfadoxine-pyrimethamine (SP) as a potential marker of H-H transmission.    Methods  The  P .  knowlesi  dihdyrofolate-reductase ( pkdhfr ) gene was sequenced from 449  P .  knowlesi  malaria cases from Sabah (Malaysian Borneo) and genotypes evaluated for association with clinical and epidemiological factors. Homology modelling using the  pvdhfr  template was used to assess the effect of  pkdhfr  mutations on the pyrimethamine binding pocket.    Results  Fourteen non-synonymous mutations were detected, with the most common being at codon T91P (10.2%) and R34L (10.0%), resulting in 21 different genotypes, including the wild-type, 14 single mutants, and six double mutants. One third of the  P .  knowlesi  infections were with  pkdhfr  mutants; 145 (32%) patients had single mutants and 14 (3%) had double-mutants. In contrast, among the 47  P .  falciparum  isolates sequenced, three  pfdhfr  genotypes were found, with the double mutant 108N+59R being fixed and the triple mutants 108N+59R+51I and 108N+59R+164L occurring with frequencies of 4% and 8%, respectively. Two non-random spatio-temporal clusters were identified with  pkdhfr  genotypes. There was no association between  pkdhfr  mutations and hyperparasitaemia or malaria severity, both hypothesized to be indicators of H-H transmission. The orthologous loci associated with resistance in  P .  falciparum  were not mutated in  pkdhfr . Subsequent homology modelling of  pkdhfr  revealed gene loci 13, 53, 120, and 173 as being critical for pyrimethamine binding, however, there were no mutations at these sites among the 449  P .  knowlesi  isolates.    Conclusion  Although moderate diversity was observed in  pkdhfr  in Sabah, there was no evidence this reflected selective antifolate drug pressure in humans.

plos one

Dihydrofolate-Reductase Mutations in Plasmodium knowlesi Appear Unrelated to Selective Drug Pressure from Putative Human-To-Human Transmission in Sabah, Malaysia