Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

Abstract

Significance Bihar, India, is the only region where arsenic contamination of drinking water coexists alongside endemic visceral leishmaniasis and where widespread resistance to pentavalent antimonial drugs (e.g., Pentostam) occurs. We have proposed that selection for parasite resistance in infected individuals exposed to environmental arsenic results in cross-resistance to the related metalloid antimony. To test this hypothesis, we have serially passaged Leishmania donovani in mice receiving arsenic in drinking water at environmentally relevant levels. In support of this hypothesis, we show that after five monthly passages, Leishmania parasites become stably resistant to Pentostam in vitro and in vivo.

Chronic arsenic exposure and microbial drug resistance

“…Resistance may arise as a result of increased expression of parasite transporter proteins that export trypanothione-Sb III conjugates out of the parasite or into intracellular organelles, reducing the intracellular accumulation of cytotoxic Sb III (8)(9)(10). Resistance may also be associated with global changes in parasite metabolism and a switch to a metabolically distinct state that facilitates survival in the mammalian macrophages (11), consistent with the data presented by Perry et al indicating that chronic exposure to arsenic may lead to increased parasite loads in susceptible animals (2). Finally, there is evidence that antimonial-resistant L. donovani may induce changes in the rate of uptake or efflux of antimonials by infected host cells, as well as changes in the host immune response (12,13).…”

“…L. donovani is the causative agent of visceral leishmaniasis (VL) or Kala-Azar, which kills many thousands of people in India each year. However, in PNAS, Perry et al (2) provide compelling evidence that Leishmania-acquired antimonial resistance in India may be attributable, at least in part, to increased arsenic contamination of the drinking water. These findings highlight how environmental factors can contribute to the emergence of microbial drug resistance and have implications for drug development.…”

“…The acquisition of antimonial resistance was associated with elevated levels of arsenic in the liver and was stable after multiple passages through arsenic-free animals. Significantly, antimonial-resistant parasites seem to be more pathogenic than antimonial-susceptible lines, even in the absence of drug selection (2,6), suggesting that antimonial/arsenic cross-resistant parasites might persist and be transferred to neighboring areas where arsenic contamination is not a problem. This finding contrasts with the more common situation where the development of drug resistance is associated with a loss of fitness in the mammalian host.…”

“…However, Perry et al (2) found no evidence that chronic exposure to subclinical levels of arsenic or even higher "toxic" levels led to a decrease in the efficacy of miltefosine in vivo, although this was not tested on cultured parasite stages or in the macrophage assay.…”

Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12/IL-10 Ratio in Macrophages Infected with Antimony-Resistant Leishmania donovani and Clears Organ Parasites in Experimental Infection

“…It is tempting to speculate that imipramine in combination with antimonials may be useful for the treatment of Sb R kala-azar cases. Pentavalent antimony remains the first line of treatment for VL in sub-Saharan Africa and Brazil (44), but not in the Bihar state in India where continuous exposure to arsenic contamination in drinking water may have contributed to the lower efficacy of antimonials because of cross-resistance (45,46). Kala-azar patients in the endemic zone of Bihar show overexpression of multidrug resistance-associated protein 1 and permeability glycoprotein in monocytes (40).…”