Evolving resistance in Southeast Asia is battering current frontline malaria drugs. Artemisinin combination therapies (ACTs) have been giving way, leading to rising treatment failures. Simultaneously, new resistance hot spots are being discovered in the region. If resistance strengthens and spreads to Africa—the nightmare scenario—what then? Alternatives are being sought, but the world has not produced a novel frontline malaria drug in over 30 years.

Today there are no good replacements for ACTs. In Thailand, a site of multiple resistance foci, the World Health Organization (WHO) now recommends Malarone, which is usually prescribed for travelers. Malarone is expensive—it’s still on patent and one of its components, atovaquone, is costly to synthesize. Worse, it is highly susceptible to resistance. Atovaquone disrupts electron transport in the mitochondria of malaria parasites by binding to very specific amino acids in the cytochrome b protein. But a single nucleotide change can alter that amino acid without destroying cytochrome b function.

Then, it’s game over: drug efficacy plummets a thousand-fold in vitro. In vivo, resistance to Malarone has been observed evolving in a single patient over the course of treatment. This seeming fragility does not bode well for Malarone’s use as a public health intervention.

Another artemisinin combination is on the horizon, one based on pyronaridine, a drug developed by China in 1970. Pyronaridine might stand a better chance than piperaquine; that drug’s rapid demise may be due to its similarity to chloroquine, which was bested by malaria long ago. However, since malaria has broken all the other ACTs, pyronaridine’s time as a component of front line therapies could be nasty, brutish, and short.

A new hope

A promising new, non-artemisinin compound, OZ439, is in phase IIa clinical trials in Southeast Asia. OZ439 clears parasites at a rate comparable to artemisinin, according to initial reports. Yet OZ439 stays in the blood stream longer, so it could potentially be the much-sought-after single dose cure for malaria—a huge boon. However, OZ439 and artemisinin have a similar mechanism of action. Both have a peroxide bridge that unleashes free radicals when it breaks down inside the parasite. Two studies have shown that the antimalarial action of artemisinin and OZ compounds depend on the peroxide bridge, suggesting a worrying possibility of cross-resistance.

Chemically, however, the two drugs “look very different—only the oxygen-oxygen bond is conserved,” notes Timothy Wells, chief scientific officer at the Medicines for Malaria Venture. “So there is every hope that they will not face the same challenge.” Other antimalarials, like chloroquine and amodiaquine, also give reasons for hope. These drugs have the same mechanism of action and resistance developed to both, but the parasites were forced to evolve different mechanisms in each case. The same could prove true with OZ439 and artemisinin, which would allow the new drug to shoulder the frontline burden globally.

But determining whether there is cross resistance will be difficult. The obvious test, treating patients with artemisinin resistant malaria, could jeopardize their lives if there turns out to be cross resistance to OZ439. “Ethically, then, it’s difficult to argue to treat artemisinin treatment failures with OZ439,” says Wells, because of this cross resistance risk. In vitro experiments have bumped up against an absence of biomarkers for artemisinin resistance. The mechanism of resistance is almost a complete mystery, and even exactly how the drug works is not comprehensively understood.

Most forms of antimalarial drug resistance have been traced back to a relatively small set of genetic adaptations. For artemisinin, the picture is more complex. Resistance to it might come not from a few mutations but a genetic network; non-genetic factors might also be involved.

Niklas Lindegard, of the Mahidol Oxford Tropical Medicine Research Unit, has devised a clever method of examining how resistant isolates handle artemisinin. His work shows that, in contrast to chloroquine (which resistant parasites defeat by rapidly pumping the toxic drug away), artemisinin appears to makes its way into parasites but breaks down more slowly in the resistant strains. Lindegard cautions that his results with OZ439 are highly preliminary but, ominously, he observed relatively sluggish drug action when it was applied to artemisinin resistant parasites.

Finding alternatives

The Medicines for Malaria Venture (MMV) has almost literally beaten the bushes and turned over every rock in search of new antimalarials. Before 2007, MMV pursued modern, rational drug design approaches based on molecular targets and compound optimization. “This turns out to be very inefficient, for a number of reasons,” explains MMV’s Wells. Drugs that targeted promising proteins that were identified through genetic studies often had no effect in actual parasites. Also, hits against molecular targets proved rare, on the order of one in a thousand. And optimization seemed to take forever.

So, in a 2007 strategy switch, MMV began mass screening of libraries totaling four million compounds, natural and synthetic. “This is actually how drug discovery was done in the 1960s,” Wells says, but now it can be done far faster.

MMV’s more recent perusal of four million compounds was enormously successful—in a way—turning up 20,000 compounds with at least some activity against malaria. To find the needle(s) in this haystack, MMV open-sourced the project. Using cluster analysis, MMV distilled the initial 20,000 hits into just 400 representative compounds. (The open access Malaria Box can be found here.) So far more than 20 groups, including both malaria and non-malaria researchers, have applied to join the program. In addition, the Gates Foundation recently invited proposals for how to "efficiently analyze, triage and prioritize anti-malarial compounds." Anyone with an idea may apply for the $100,000 grants.

Fundamentally, however, despite 21st century, state-of-the-art efforts, the world has not discovered a frontline antimalarial with a novel mode of action in more than three decades.

Artemisinin was, in a sense, rediscovered in the early 1970s. The naturally occurring substance comes from Chinese wormwood, Artemisia annua. A text dating to the Ming dynasty recommended artemisinin, or q?ngh?o, for fevers. Chinese scientists tripped into its antimalarial properties while screening about 2,000 ancient recipes based on 600-odd plants.

What reinforcement we may gain from hope

OZ439 might turn out to be effective against artemisinin-resistant parasites. The new drug is a ways from approval and a suitable partner drug needs to be found to create a combination therapy, such as those used for artemisinin. Matchmakers are busy, although arrangements are far from final. Nonetheless, OZ439 could potentially blow away the “last man standing,” the pockets of resistance that now exist in Southeast Asia. Or, if too late to prevent the spread of artemisinin resistance, OZ439 could replace ACTs wherever their efficacy declines.

But the best chance for victory might lie in perpetually deferring defeat, slowing the spread of resistance until some major aspect of the situation changes: a remarkably timely breakthrough in science, say, or development of a more complete health care infrastructure in sub-Saharan Africa.

Whether we are watching the early stages of a multi-billion person global health disaster or just another cycle in the endless contest against pathogenic evolution is unclear. Twenty years ago, in 1992, researcher Nick White warned, “there is a real prospect of completely untreatable malaria within the next ten years.” Artemisinin saved the day, and lots of people are trying to find an equivalent savior.

At the moment, however, one thing is clear: the advantage appears to lie with the parasites.