First artemisinin based malaria drug may meet resistance, expert says

Jan 8 2009

This year, the U.S. Food and Drug Administration is expected to approve the first malaria drug to contain artemisinin, a wormwood derivative from China that has proven effective for malaria in Africa and Asia.

Although there are only about 1,500 reported cases of malaria treated in this country each year, this approval would also make the drug available to the military and to Americans planning to go abroad. However, worldwide malaria is still one of the most serious infectious diseases, affecting 2 to 3 billion people, with up to two million deaths annually.

The drug, named Coartem, is made by the Swiss company Novartis. It combines artemether, an artemesinin derivative, with lumefantrine, a drug developed by Chinese scientists, which does not kill parasites as quickly but lingers in the blood a while longer. By mopping up parasites that artemisinin misses, lumefantrine helps prevent resistance that would defeat the drug, as has occurred with other therapies like chloroquine.

According to University of Pennsylvania pharmacologist Doron Greenbaum, Ph.D., although the exact mechanism by which artemisinin kills parasites is still open to considerable debate, the drug likely acts against one or more protein targets that may make it susceptible to resistance that has developed to most other drugs. Drug resistance to artemisinin has already been shown to occur in the laboratory, and reports have already surfaced about potential resistance in malaria endemic regions like southeast Asia. Thus the potential success of Coartem treatment for malaria should be greeted with cautious optimism knowing that resistance is likely to arise and that other new drugs will need to be developed quickly.

Dr. Greenbaum recently reported that small molecule defensin-mimetic compounds discovered by Radnor, Penn.-based biopharmaceutical company PolyMedix, irreversibly kill P. falciparum while sparing human red blood cells. Plasmodium species are responsible for the nearly five hundred million cases of malaria worldwide and as many as two million deaths, most of them in children. As with antimicrobial agents, first-line malaria agents are losing effectiveness due to development of resistance to drugs by the target organisms.

Dr. Greenbaum demonstrated that PolyMedix's compounds kill P. falciparum irreversibly, meaning the cells do not recover when the agent is depleted. Irreversible killing distinguishes a "cidal," or true killing mechanism, from a "static" mechanism that holds the infectious agent at bay while the body's immune system fights off the infection. "If we treat for ten hours and remove the compound, the parasites never recover," notes Dr. Greenbaum. Many antimicrobial and antifungal drugs are of the static variety.

PolyMedix antibiotics are small-molecule non-peptide mimetics of natural host defense peptides that higher animals use to fight infections. In humans these molecules, known as defensins, are about thirty amino acids in length. Although structurally quite dissimilar, defensins and PolyMedix's compounds share a common characteristic that is responsible for their anti-infective activity. Both molecules are facially amphiphilic, meaning they possess several polar, or charged chemical groups on one side of the molecule, and hydrophobic groups on the other side. They are believed to work by inserting themselves inside the lipid bilayers of cells that are deficient in cholesterol, thereby causing the cells to rupture and die. Therefore these molecules kill pathogens by targeting membranes rather than proteins. Dr. Greenbaum hypothesizes that this mechanism is employed against both bacteria and Plasmodium.

"As far as we know, the PolyMedix defensin-mimetics are the only anti-infectives with such a biophysical mechanism of action, directly targeting the membrane, whether bacterial, fungal, or parasitic," says Dr. Greenbaum. "This makes resistance unlikely to develop. Any biochemical/protein-based mechanism of action is susceptible to resistance via efflux or target mutation."

The complex lifecycle of P. falciparum makes malaria difficult to treat once it is established. The organism typically enters the body through a mosquito bite, soon takes residence in the liver, and then migrates to red blood cells. It is the last stage that gives rise to the chronic disease known as malaria. During their lifecycle the organisms take on several distinct morphologic and biological forms. PolyMedix's defensin-mimetics show very high killing efficacy against all stages of red cell infection. The next step is to see if the compounds can clear infection in a mouse model, in the liver phase, as well as the red cell stage.

PolyMedix's lead defensin-mimetic antibiotic compound, PMX-30063, is currently in human clinical testing, and is intended to be developed as a broad anti-Staph agent. The first Phase I clinical results with PMX-30063 were announced in December 2008.