Defective DNA repair as a potential mechanism for the rapid development of drug resistance in Plasmodium falciparum.
The development and spread of highly drug-resistant parasites pose a central problem in the control of malaria. Understanding mechanisms that regulate genomic stability, such as DNA repair, in drug-resistant parasites and during drug treatment may help determine whether this rapid onset of resistance is due to an increase in the rate at which resistance-causing mutations are generated. This is the first report to demonstrate DNA repair activities from the malaria-causing parasite Plasmodium falciparum that are specific for ultraviolet light-induced DNA damage. The efficiency of DNA repair differs dramatically among P. falciparum strains with varying drug sensitivities. Most notable is the markedly reduced level of repair in the highly drug-resistant W2 isolate, which has been shown to develop resistance to novel drugs at an increased rate when compared to drug-sensitive strains. Additionally, the antimalarial drug chloroquine and other quinoline-like compounds interfered with the DNA synthesis step of the repair process, most likely a result of direct binding to repair substrates. We propose that altered DNA repair, either through defective repair mechanisms or drug-mediated inhibition, may contribute to the accelerated development of drug resistance in the parasite.
Trotta
Richard F
RF
Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA. richard.trotta@us.army.mil
Brown
Matthew L
ML
Terrell
James C
JC
Geyer
Jeanne A
JA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D015767:Mefloquine / Q000494:pharmacology / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects*; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use; D011803:Quinine / Q000494:pharmacology / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use; D000077145:Sulfanilamide; D013424:Sulfanilamides / Q000494:pharmacology / Q000627:therapeutic use; D014466:Ultraviolet Rays
D000962:Antimalarials; D037621:Artemisinins; D010616:Phenanthrenes; D012717:Sesquiterpenes; D013424:Sulfanilamides; D000077145:Sulfanilamide; D002738:Chloroquine; C031327:artemisinin; D011803:Quinine; C023768:halofantrine; D015767:Mefloquine; D011739:Pyrimethamine