Novel mechanism of drug resistance in kala azar field isolates

Clinical resistance to pentavalent antimonial drugs in the form of sodium antimony gluconate (SAG) has become a major problem in the treatment of kala azar (visceral leishmaniasis) in India. The mechanism of resistance is unclear in these clinical isolates, although work has been conducted with Leishmania species mutants selected in vitro by stepwise increase of drug concentration, using antimony-related metal arsenic and, more recently, SAG. In the present study, we investigated the molecular aspect of drug resistance in clinically confirmed SAG-resistant field isolates. Our results show that the mechanisms of resistance postulated for laboratory mutants of Leishmania species are not operating in field isolates of Leishmania donovani. Instead, we identified a novel gene amplified in these drug-resistant parasites whose locus is on chromosome 9. The significant finding was that this isolated fragment confers antimony resistance to wild-type Leishmania species after transfection. We speculate that protein phosphorylation may play a role in signal transduction pathway in the parasite after exposure to drug-conferring resistance.