A recent collaborative study by scientists from India, Brazil and Belgium has found a new agent, voacamine, to be effective against even drug-resistant Indian strains of Leishmania. The study, was published in the journal Biochemical Pharmacology.
Voacamine is an indole alkaloid – a bitter chemical – extracted from the bark of the crêpe jasmine shrub (Tabernaemontana coronaria), which is a common house and garden plant in India. The chemical was reported as being moderately effective in killing Plasmodium falciparum, the causal agent of cerebral malaria. Since Leishmania and Plasmodium are similar, both being protozoan parasites, Hemanta K. Majumder and Sibabrata Mukhopadhyayfrom the CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, initiated a study to study the effects of voacamine on Leishmania donovani.
They found that not only was voacamine effective in killing Leishmania donovani parasites growing in a culture of human cells, but it was also able to clear visceral leishmaniasis infections from mice in three weeks. What is even more important, is that voacamine could kill Leishmania strains that are resistant to several drugs currently used to treat the disease.
The paper further elucidates the mode of voacamine action on Leishmania by pinpointing the drug’s target – an enzyme called Topoisomerase 1B which helps DNA maintain its topological structure, during different cellular processes such as replication or transcription. When topoisomerase 1B is bound to DNA, it forms a ‘cleavage complex’, to which voacamine binds. Once bound, voacamine ‘stabilises’ this complex. When the cell’s replication or transcription machinery collides with this ‘stabilised complex’, it causes breaks in the DNA that ultimately lead to the death of the parasite.
“We have long been interested in studying the Topoisomerase 1B from Leishmania as a possible drug target, since it is very different from its human counterpart. This difference makes it possible for us to look for drug molecules that could target the parasite specifically, without affecting human cells,” says Majumder. “Although voacamine can kill some kinds of cancer cells, it shows almost no toxicity to normal human cells. Since it is required in much lower doses to clear Leishmania infections, it has potential as a drug candidate to treat leishmaniasis,” he adds.
Leishmaniasis is a neglected tropical disease spread by the bite of blood-sucking sandflies, and is endemic in 65 countries, which puts about 1 billion people at risk of infection. Of the 200,000 to 400,000 cases reported annually, roughly 90% of new cases occur in India, Nepal, Bangladesh, Sudan and Brazil.
The most severe form of leishmaniasis, called visceral leishmaniasis or kala azar is rife in Bihar, which records 90% of Leishmania infections in India. No vaccine is available against leishmaniasis as of now. The situation is rendered even uglier with the emergence of drug-resistant strains of Leishmania that leave conventional agents such as pentavalent antimonials, miltefosine and amphotericin B useless in combating the disease.
“This is the first report demonstrating the efficacy of a compound to reduce the burden of drug resistant parasites, unresponsive to SAG (Sodium Antimony Gluconate), amphotericin B and miltefosine, in experimental BALB/c mice model of visceral leishmaniasis,” says Neeloo Singh, a Professor from the Central Drug Research Institute, Lucknow, who works on leishmaniasis. “Since drug resistance in leishmaniasis is a grave problem, voacamine is a welcome entrant as a prospective anti-leishmanial,” she adds.
Somenath Roy Chowdhury, a member of Majumder’s team at CSIR-IICB is excited about using voacamine against parasites other than L. donovanii. “Voacamine was also effective against intracellular forms of the Brazilian strain of Leishmania amazonensis, the pathogen for cutaneous leishmaniasis; and the epimastigotes of Trypanosoma cruzi, the pathogen for Chagas diseases”, he says.
Majumder, however, cautions that to bring voacamine into the market as a drug, many more tests and trials are necessary. “Voacamine extraction from its plant source may also not be very viable for large-scale drug production, so a chemical method for voacamine synthesis will be needed to bring down manufacturing costs. We have completed the first, very important step of drug discovery. But from here to actual practical use of voacamine in treating leishmaniasis, there is much more to be done,” he adds.