Emergence of an unusual sulfadoxine-pyrimethamine resistance pattern and a novel K₅₄₀N mutation in dihydropteroate synthetase in Plasmodium falciparum isolates obtained from Car Nicobar Island, India, after the 2004 Tsunami

Abstract

Background: Enormous amounts of drugs were used to contain the outbreak of infectious diseases in areas of India affected by the tsunami in December 2004. The impact of this drug use on the Plasmodium falciparum population needs to be investigated. Methods: The nucleotide sequence of the pfcrt, pfdhps and pfdhfr genes was determined for 229 clinical P. falciparum isolates collected from patients on Car Nicobar Island at 6 different time points between May 2004 and May 2008. Results: Over time, there was an increase in the proportion of the P. falciparum population that had mutations in the pfcrt, pfdhps and pfdhfr genes associated with higher levels of chloroquine, sulfadoxine, and pyrimethamine resistance, respectively. However, the parasites collected during October 2005 had mutations associated with a lower level of pyrimethamine resistance and a higher level of sulfadoxine resistance (a rare combination), as well as a novel K540N mutation in P. falciparum dihydropteroate synthetase (PfDHPS). The emergence of this parasite population coincided with the widespread use of an additional antifolate drug, trimethoprim-sulfamethoxazole, to treat other infections during January-March 2005. Molecular modeling revealed that the sulfadoxine binding affinity of the new PfDHPS triple mutant A₄₃₆ G₄₃₇ N₅₄₀A₅₈₁A₆₁₃ was similar to that of A₄₃₆ G₄₃₇ E₅₄₀A₅₈₁A₆₁₃ (bold type indicates mutated amino acids). Conclusions: The use of 2 antifolate drugs in combination should be avoided to prevent the selection of parasites with newer mutations and altered drug susceptibilities.