Novel point mutations in sulfadoxine resistance genes of Plasmodium falciparum from India.
Point mutations in the dhfr and dhps genes of Plasmodium falciparum are associated with pyrimethamine and sulfadoxine resistance respectively. In this study we have analyzed these genes from Bikaner (situated in North-West region of India), where both uncomplicated and severe manifestations of P. falciparum malaria are seen. A majority of isolates showed double mutant allele for DHFR. In contrast, the only reported mutation present in DHPS was A437G in few isolates. In addition, three novel non-synonymous mutations were observed in the PfDHPS from this region viz., S587F, N666K and C668W. The mutations at the 666 and 668 codon seem to form a bend in the big loop region of the DHPS enzyme and may affect the binding of the drug to the enzyme. Molecular docking of sulfadoxine to this mutated structure indicates reduction in its binding affinity to this enzyme.
Garg
Shilpi
S
Centre for Biotechnology, Biological Sciences Group, Birla Institute of Technology and Science, Pilani, Rajasthan, India.
Saxena
Vishal
V
Kanchan
Swarna
S
Sharma
Pooja
P
Mahajan
Siddharth
S
Kochar
Dhanpat
D
Das
Ashis
A
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D016054:DNA, Protozoan; D004094:Dihydropteroate Synthase / Q000235:genetics; D004351:Drug Resistance; D006801:Humans; D007194:India; D016778:Malaria, Falciparum / Q000469:parasitology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D000962:Antimalarials; D016054:DNA, Protozoan; D015800:Protozoan Proteins; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase