Mechanisms of drug resistance in malaria.

Plasmodium falciparum causes the most severe form of human malaria which directly results in over two million deaths per year. As there is not yet a useful vaccine against this disease the major form of treatment and control is the use of chemotherapeutic agents. Unfortunately the parasite has managed to devise mechanisms that allow it to evade the action of almost all the antimalarials in our arsenal. The antifolate drugs include the dihydrofolate inhibitors pyrimethamine and proguanil as well as the sulfones and sulfonamides. These antimalarials act on enzymes in the folate pathway. The mechanism of resistance to these compounds involve mutations in the target enzyme that decrease the affinity of binding of the drug. A second major group of antimalarials include the quinine-like compounds. Quinine was one of the first compounds used to treat malaria and the related drug chloroquine is the most important antimalarial. Mefloquine and halofantrine were developed in response to major problems with the spread of chloroquine resistance. Chloroquine resistance is due to the ability of the parasite to decrease the accumulation of the drug in the cell. The exact mechanism that allows this is still under investigation although at least one protein has been identified that affects the accumulation of this important antimalarial.