Short communication: Prevalence of mutations associated with resistance to atovaquone and to the antifolate effect of proguanil in Plasmodium falciparum isolates from northern Ghana.
Atovaquone-proguanil has recently been introduced for the treatment and prophylaxis of malaria. However, resistance of Plasmodium falciparum is increasingly reported. We assessed P. falciparum polymorphisms associated with resistance to atovaquone (cytochrome b, cytb) and to cycloguanil, the active compound of proguanil (dihydrofolate reductase, dhfr) in 100 isolates from northern Ghana. None of these exhibited cytb codon 268 mutations. Moreover, no dhfr V16A, S108T or I164L mutations linked with cycloguanil resistance were detected. However, dhfr triple mutants (S108N-I51L-C59R) conferring resistance to proguanil and sulphadoxine-pyrimethamine were seen in 51% of the isolates. In northern Ghana, P. falciparum cytb codon 268 mutations associated with atovaquone resistance are absent. Although proguanil appears to act synergistically with atovaquone in a way different from its antifolate property, the abundance of dhfr polymorphisms will likely compromise the prevention of dissemination of atovaquone-resistant parasites once emerged.
Muehlen
Marion
M
Institute of Tropical Medicine, Charité, Humboldt University, Berlin, Germany. marion.muehlen@charite.de
Schreiber
Jonas
J
Ehrhardt
Stephan
S
Otchwemah
Rowland
R
Jelinek
Tomas
T
Bienzle
Ulrich
U
Mockenhaupt
Frank P
FP
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone; D002675:Child, Preschool; D045303:Cytochromes b / Q000235:genetics; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005869:Ghana / Q000453:epidemiology; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000517:prevention & control; D008297:Male; D009154:Mutation; D009285:Naphthoquinones / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D002727:Proguanil / Q000494:pharmacology / Q000627:therapeutic use; D011739:Pyrimethamine / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014227:Triazines / Q000494:pharmacology*
D000962:Antimalarials; D004338:Drug Combinations; D005493:Folic Acid Antagonists; D009285:Naphthoquinones; D014227:Triazines; C026009:cycloguanil; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D045303:Cytochromes b; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D053626:Atovaquone; D011739:Pyrimethamine