Quinoline antimalarials: mechanisms of action and resistance.
The quinoline-containing antimalarial drugs, chloroquine, quinine and mefloquine, are a vital part of our chemotherapeutic armoury against malaria. These drugs are thought to act by interfering with the digestion of haemoglobin in the blood stages of the malaria life cycle. Chloroquine is a dibasic drug which diffuses down the pH gradient to accumulate about a 1000-fold in the acidic vacuole of the parasite. The high intravacuolar concentration of chloroquine is proposed to inhibit the polymerisation of haem. As a result, the haem which is released during haemoglobin breakdown builds up to poisonous levels, thereby killing the parasite with its own toxic waste. The more lipophilic quinolinemethanol drugs, mefloquine and quinine, are not concentrated so extensively in the food vacuole and probably have alternative sites of action. The technique of photoaffinity labelling has been used to identify a series of proteins which interact specifically with mefloquine. These studies have led us to speculate that the quinolinemethanols bind to high density lipoproteins in the serum and are delivered to the erythrocytes where they interact with an erythrocyte membrane protein, known as stomatin, and are then transferred to the intracellular parasite via a pathway used for the uptake of exogenous phospholipid. The final target(s) of quinine and mefloquine action are not yet fully characterised, but may include parasite proteins with apparent molecular weights of 22 kDa and 36 kDa. As resistance to the quinoline antimalarials rises inexorably, there is an urgent need to understand the molecular basis for decreased drug sensitivity. A parasite-encoded homologue of P-glycoprotein has been implicated in the development of drug resistance, possibly by controlling the level of accumulation of the quinoline-containing drugs. As our molecular understanding of these processes increases, it should be possible to design novel antimalarial strategies which circumvent the problem of drug resistance.
Foley
M
M
School of Biochemistry, La Trobe University, Victoria, Australia.
Tilley
L
L
D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology; D004351:Drug Resistance; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D015767:Mefloquine / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism; D011803:Quinine / Q000378:metabolism / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*
D000962:Antimalarials; D001798:Blood Proteins; D006454:Hemoglobins; D008565:Membrane Proteins; D011804:Quinolines; C036860:STOM protein, human; D002738:Chloroquine; D011803:Quinine; D015767:Mefloquine