Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria.

• DOI: 10.1073/pnas.87.8.3018
• Publication Date: 2006-05-31T07:38:04Z
• Authors: D S Peterson; W K Milhous; T E Wellems
• Keywords: Proguanil; Dihydrofolate reductase; Antifolate

Proguanil and pyrimethamine are antifolate drugs with distinct chemical structures that used commonly in the prophylaxis treatment of Plasmodium falciparum malaria. Clinical reports field studies have suggested some parasites refractory to proguanil can be treated pyrimethamine, vice versa. Analysis P. dihydrofolate reductase (DHFR) from different reveals structural basis for differential susceptibility these drugs. Parasites harboring a pair point mutations Ala-16 Val-16 Ser-108 Thr-108 resistant cycloguanil (the active metabolite proguanil) but not pyrimethamine. A single Asn-108 mutation, on other hand, confers resistance only moderate decrease cycloguanil. Significant cross-resistance both occurs having include Ser-108----Asn-108 Ile-164----Leu-164. These results reflect suggest fine differences binding within site cavity DHFR. Alternative inhibitors, alone or combination, may effective against strains cycloguanil- pyrimethamine-resistant