Taking Aim at Parasites--and Drug Resistance

Martin is a contributing news editor and writer based in Amsterdam

Call it a therapeutic twofer. A group of new drugs against malaria does more than just kill parasites; it may also restore the efficacy of a generation of older drugs called quinolines to which parasites around the world have become resistant.

Over the decades, malaria parasites have developed resistance to almost every drug humans have thrown at them. There are signs of emerging resistance even to the latest generation of drugs being rolled out, the highly effective artemisinin-based drugs, triggering worries that the world might soon be left empty-handed (Science, 19 December 2008, p. 1776). To prevent this, health experts say that instead of "monotherapies," new drugs should always be given in combination with other, existing drugs, which makes it harder for the parasite to elude them.

There are other ways of fighting resistance. For a group of malaria drugs called the quinolines--which includes former mainstays such as quinine and chloroquine--scientists have tried to develop "resistance reversal agents," secondary drugs that undo the resistance. This is possible because quinolines are active inside a cell organelle called the digestive vacuole; resistance occurs when the parasite finds ways of keeping the drug out of the vacuole. A reversal agent works by restoring the drug's access, but most of these agents only work at high doses, which would increase the risk of neurological side effects, says Jane Kelly, a malaria researcher at the Portland Veterans Affairs Medical Center in Oregon. As with new drugs, the reversal agents would be a stronger weapon if combined with existing drugs.

In response, Kelly and her colleagues developed some double-edged swords. The molecules, called acridones, act as powerful resistance reversal agents, but another region within each of them has malaria-killing activity itself. In a paper published online by Nature this week, the team showed that one of the drugs, called T3.5, could restore the action of two quinolines in resistant parasites at low levels; it could also cure mice with malaria by itself. Combined with a relatively new quinoline such as piperaquine--to which resistance is still rare--the drug, or a chemical cousin, might form a cheap and safe new combination therapy, says Kelly.

The study is "a useful contribution to the field," and packing two modes of action into one drug has several advantages, says Christophe Biot, a malaria researcher at the Université des Sciences et Technologies in Lille, France. For instance, it makes administration easier and cheaper. But he says he would like to see more data on toxicity and cautions that the acridones still have a long way to go before they're ready for use in humans.

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