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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 49; pp. 19932 - 19937
• Main Authors: Perry, Meghan R., Wyllie, Susan, Raab, Andrea, Feldmann, Joerg, Fairlamb, Alan H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03-12-2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Series: From the Cover
• Subjects: Amastigotes; Animals; Antimony; Antimony Sodium Gluconate; Antiprotozoal Agents - metabolism; Arsenic; Arsenic - toxicity; Biological Sciences; Cell Line; Contamination; Drinking water; Drinking Water - analysis; Drug resistance; Drug Resistance - drug effects; Environmental Exposure - adverse effects; India; Leishmania - drug effects; Leishmania donovani; Leishmaniasis, Visceral - drug therapy; Liver; Macrophages - drug effects; Mass Screening; Mass Spectrometry; Medical treatment failures; Mice; Mice, Inbred BALB C; Parasites; Potable water; Rodents; Spleen; Visceral leishmaniasis; Water Pollutants, Chemical - toxicity; India; India, Bihar; drug resistance; treatment failure; sodium antimony gluconate; environmental pollution
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1311535110

The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg⋅mL ⁻¹ Pentostam compared with the control passage group (38.5 μg⋅mL ⁻¹) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.