title: 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 A436G437N540A581A613 was similar to that of A436G437E540A581A613 (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
authors.affiliation: Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Vanshika
authors.initials: V
authors.lastname: Lumb
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Das
authors.forename: Pooja
authors.initials: P
authors.lastname: Mittra
authors.forename: Anwar
authors.initials: A
authors.lastname: Ahmed
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
authors.forename: Aditya P
authors.initials: AP
authors.lastname: Dash
authors.forename: Shiv S
authors.initials: SS
authors.lastname: Singh
authors.forename: Yagya D
authors.initials: YD
authors.lastname: Sharma
mesh_terms: D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D020134:Catalytic Domain; D004094:Dihydropteroate Synthase / Q000737:chemistry / Q000235:genetics*; D004190:Disasters; D004338:Drug Combinations; D004351:Drug Resistance; D005843:Geography; D007194:India / Q000453:epidemiology; D026901:Membrane Transport Proteins / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D055871:Tidal Waves; D013997:Time Factors
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine