trypanosome showing acidocalcisome organelles

Drugs that have already been approved for treatment of osteoporosis may form the basis of the next generation of antimalarial compounds, according to a team of British, American and Venezuelan researchers. In addition to their activity against Plasmodium falciparum, a causative agent of malaria, the compounds, called bisphosphonates, appear to kill trypanosomes, Leishmania, and Toxoplasma gondii. Together, these parasites infect over 500 million people annually worldwide, mostly in the tropics.

The researchers, whose work appears in the 15 March issue of the Journal of Medicinal Chemistry, had previously performed structural studies on protozoan parasites and discovered large amounts of pyrophosphate stored in organelles which they named acidocalcisomes. “We found it logical to test hydrolytically stable analogs of pyrophosphate — bisphosphonates — against the parasites, and were encouraged by the anti-parasitic activity we found,” says study author Roberto Docampo from the University of Illinois Urbana-Champagne. Docampo adds, “organelles similar to acidocalcisomes, called volutin granules, have been described in bacteria and fungi,” suggesting that the bisphosphonates may be useful against a wide range of pathogens.

Bisphosphonates already approved for human use include Merck's Fosamax, Procter and Gamble's Actonel, and Novartis' Aredia. Fosamax, which has been prescribed to over 3 million patients since its introduction in 1995, is currently the leading osteoporosis drug and enjoys annual worldwide sales of over $1 billion.

Having demonstrated the potential of bisphosphonates against parasites in vitro, the researchers are now testing the drugs in animal models of parasitic diseases. Docampo says that the animal results have been promising so far, particularly against visceral and cutaneous leishmaniasis.

Eric Oldfield, a University of Illinois researcher and co-author, states that “new drugs are urgently required in the less developed nations, since the parasites are becoming drug resistant at an alarming rate.” So far, however, the researchers have not determined how readily parasites will develop resistance to bisphosphonates.

Another concern is that, while Fosamax and its relatives have been blockbuster drugs for treating osteoporosis in developed countries, the drugs' prices remain out of reach for the developing world, where parasitic diseases are concentrated. Still, Docampo is hopeful that pharmaceutical companies will be willing to offer discounts to poor countries: “The synthesis of these drugs is not expensive. This could be a case where the intervention of charitable organizations could have a major role.”