July 22, 2016
2 min read

Good news: Antimalarial drug resistance may come at a cost to the parasite

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As is the case with many infectious diseases, drug resistance is a major problem in malaria. In particular, Plasmodium falciparum, the most virulent human malaria parasite, has demonstrated resistance to all available antimalarial agents. Of particular concern is resistance to artemisinin-based combination therapy, now the standard to treat uncomplicated falciparum malaria. Resistance to both artemisinins and partner drugs has been demonstrated in Southeast Asia, increasing treatment failure in that region and fueling fears that resistance will spread to other areas.

Another important antimalarial drug is Malarone (atovaquone/proguanil, GlaxoSmithKline), which is an effective therapy for malaria and also is widely used for the prevention of malaria in travelers to malaria-endemic areas. Atovaquone/proguanil is generally highly efficacious for treatment and prevention, but both components select quite easily for resistance when used as monotherapies. Atovaquone selects for resistance particularly readily, presumably because it has a mitochondrial target, and limited mitochondrial proofreading in DNA replication facilitates rapid mutation of drug targets. Atovaquone/proguanil is quite expensive, and while commonly used by travelers, it is not widely used in endemic countries, probably helping to limit the spread of resistance. Nonetheless, there is worry that atovaquone resistance will become widespread. But, will atovaquone-resistant parasites be able to spread?

Philip J. Rosenthal

Malaria transmission entails a complex life cycle, including the liver stage that follows inoculation by an infected mosquito, the asexual erythrocytic stage that is responsible for clinical manifestations of malaria, and sexual stages when the parasite is transmitted to anopheline mosquitoes, initiating a mosquito cycle that culminates in production of infectious sporozoites. It has been hypothesized that parasite mutations that mediate drug resistance may come at some cost to parasite fitness. This fitness cost may be manifested as decreased growth in erythrocytes, and there is evidence to support decreased development, compared with wild type, of some resistant parasites in erythrocytes. In addition, a fitness cost of resistance might be seen in mosquito stages. In that case, parasites might develop normally in humans, with consequent clinical illness, but they might not be able to effectively be transmitted via mosquitoes.

Goodman and colleagues explored this latter possibility in rodent P. berghei and human P. falciparum malaria parasites. In a series of elegant experiments, they showed that resistant parasites maintained erythrocyte-stage infection, but they could not complete development through mosquito stages to infectious sporozoites. When mutant parasites were crossed with wild-type parasites — a procedure that allows parasites to exchange genetic information and produce hybrid offspring — no progeny of the crosses were atovaquone-resistant, and the failure to transmit resistance was due to the mitochondrial gene mutation that mediates atovaquone resistance. Most of these studies were done in P. berghei, which only infects rodents, but infectivity to mosquitoes was shown to be similarly limited in atovaquone-resistant P. falciparum. Thus, it appears that parasites that are resistant to atovaquone, while capable of causing potentially life-threatening malaria, are not readily transmitted to others via the mosquito vector. This is good news. Atovaquone-resistant malaria may not spread due to a mosquito-stage bottleneck. Of course, resistance to other drugs is widespread — evidence that resistance is not uniformly blocked at the mosquito stage. Further study of impacts of resistance on malaria transmission, in particular for artemisinin-resistant parasites, will help us to sort out the likelihood of the spread of resistance to different drugs, and thus to best optimize malaria treatment and control strategies.

Disclosure: Rosenthal reports serving as a consultant for Novartis.