March 3, 2015 — Drug resistance is a major public health challenge for malaria treatment and eradication. In new research, Dyann Wirth and colleagues have found new ways that the parasite that causes malaria—Plasmodium falciparum—is able to develop resistance to the antimalarial drug halofuginone over time.
It’s been known that P. falciparum develops resistance to antimalarial drugs through genetic mechanisms. Your new research uncovered a new model of how the malaria parasite can also develop resistance through non-genetic means. How did you and your colleagues discover this?
Jonathan Herman, an MD/PhD student in my lab, became interested in understanding the process by which an organism goes from being sensitive to a drug to being resistant. In the past we’d looked at the endpoint—the point at which the organism had already become resistant—but we never followed the organism’s path over time, over generations, to see how resistance developed. Using DNA sequencing, Jon characterized the features of a malaria parasite population over several generations. He essentially ‘followed’ evolution in the test tube.
Jon discovered that the mutation that occurs in the malaria parasite—which confers drug resistance—actually wasn’t the first thing that happened. In fact, the first adaption in the parasite was a change in the concentration of an amino acid called proline, which occurred at a much earlier stage in the parasite’s evolutionary process. The parasite floods itself with this amino acid as a way of neutralizing the effect of the drug, in this case, halofuginone. This mechanism showed that an organism can adapt relatively early on to a drug through non-genetic means.
How important is this discovery and how might it affect the development of malaria drugs?
Extremely important, as the mechanism may exist for other drugs as well as for other organisms. We think this is an unexplored area of the emergence of drug resistance that could perhaps give us new avenues to think about better ways of combining drugs to tackle resistance. Now that we know about the activity of this early resistance mechanism, perhaps we can target it with another drug, in tandem with halafuginone, and have a way to hit the parasite in two ways that we would never have thought of doing before.
What’s the next step in this research?
In this particular case, we need to understand more about the mechanism by which the parasite adapts to the drug. But we’re also going to try to look at this same evolutionary process using other classes of antimalarial drugs to see if this is a more general phenomenon. Maybe there’s a class of drugs for which this adaptive response occurs, or perhaps it’s true for all drugs but no one’s ever looked before.