Arsenic Exposure May Be Creating A Drug-Resistant Parasite

In parts of the Indian subcontinent, the only source of drinking water is groundwater that naturally contains arsenic. Lacking the means to remove the toxic substance, millions of people in these regions succumb to arsenic poisoning each year, dramatically increasing their risk of skin disease, heart disease, and cancer.

A recent study by an international team brings more bad news for those exposed to arsenic in drinking water: The troublesome chemical element may be helping a parasite develop drug resistance.

Transmitted to humans through the bites of infected female sand flies, the Leishmania donovani parasite causes a disease—visceral leishmaniasis—that afflicts close to 300,000 people in India each year and is fatal if not treated. For more than six decades, drugs based on antimony had been widely used to treat visceral leishmaniasis, which can cause fever, anemia, and swelling of the liver and spleen. But their efficacy has inexplicably declined in India.

For this reason, since 2005 the Indian government no longer recommends the use of antimony-based drugs. Their use continues, however, because alternatives such as the antifungal drug amphotericin B and the antiprotozoal drug miltefosine are more expensive. The results have been unfortunate. For example, in the Indian state of Bihar, where the disease is endemic, cure rates of patients taking antimony-based drugs dropped almost 60% during the period 2006 to 2010.

The new study suggests that exposure to arsenic in drinking water may have caused the treatment failure observed in Bihar by enabling the Leishmania parasite to develop resistance to antimonial drugs (PLOS Neglected Trop. Dis. 2015, DOI: 10.1371/journal.pntd.0003518).

Pointing out a silver lining to these findings, Meghan R. Perry, a member of the team that carried out the study, says that such a link between arsenic exposure and drug resistance in Leishmania parasites opens a new avenue of research. How environmental pollutants exacerbate infectious diseases “is an important and under-researched area that affects some of the world’s most vulnerable populations,” says Perry, who is now a lecturer at the University of Edinburgh, in Scotland.

The study should alert scientists studying antimicrobial resistance that they should consider the effect of the environment on microbial selection for drug resistance, adds team leader Alan H. Fairlamb, a biochemistry professor at the University of Dundee, in Scotland.

In trying to understand what triggered the failure of antimonial drugs in Bihar, Fairlamb and colleagues focused on two pieces of information. One was their observation of the simultaneous occurrence of visceral leishmaniasis, arsenic contamination, and failure of antimonial drugs in 10 of 38 districts in Bihar during 2006 to 2010. Another is a previous study showing that arsenic-exposed Leishmania parasites grown in the lab develop resistance to antimony-based drugs (Mol. Biochem. Parasitol. 1994, DOI: 10.1016/0166-6851(94)90095-7).

To test the hypothesis, Fairlamb’s team began by studying arsenic-exposed mice infected with the Leishmania parasite. The researchers found that such mice become resistant to high doses of an antimony-based drug called sodium stibogluconate (Pentostam) (Proc. Natl. Acad. Sci. USA 2013, DOI: 10.1073/pnas.1311535110). They concluded that treatment failed because the parasites became tolerant to the drug, which is a cyclic ester of gluconic acid and antimonic acid.

In the new study, the team examined the medical records of 110 patients treated with sodium stibogluconate in 2006–10. The patients ranged in age from three to 60 years and came from a Bihar district where more than 40% of the tube wells from which residents draw their drinking water contain arsenic at levels exceeding the World Health Organization’s limit of 10 µg/L.

The retrospective analysis revealed a failure rate of 56% for sodium stibogluconate. The drug did not work for 62 of the 110 patients: Ten died of visceral leishmaniasis, 40 showed no clinical improvement, eight relapsed, and four stopped treatment because of severe side effects. Treatment was more likely to fail for patients from high-arsenic areas (>10 µg/L) than for those from low-arsenic areas (<10 µg/L).

To explain the findings, the team turned to the chemical similarity of antimony and arsenic, which belong to the same group of the periodic table.

According to Fairlamb, the mechanism by which antimony-based drugs treat visceral leishmaniasis is not fully understood, but it is generally accepted that the pentavalent antimony in these drugs is first reduced to trivalent antimony in cells of the host or the parasite. Trivalent antimony disrupts the metabolism of trypanothione, a sulfur-containing molecule that Leishmania parasites use to defend against oxidative stresses, Fairlamb explains. In the parasite, trypanothione is reduced to dihydrotrypanothione, which forms complexes with trivalent antimony and with the chemically similar trivalent arsenic. Such binding sequesters dihydrotrypanothione, making the parasite more vulnerable to oxidative stress.

In people chronically exposed to arsenic through their drinking water, trivalent arsenic is abundantly available to react with dihydrotrypanothione. Fairlamb speculates that long-term exposure to arsenic favors gene mutations—such as those that increase dihydrotrypanothione biosynthesis—that would enable the parasites to develop resistance to arsenic. Because arsenic is closely related to antimony, parasites that tolerate arsenic would also survive antimony exposure. Called cross-resistance, the phenomenon is commonly observed with antibiotics and pesticides.

The study has a major gap, however, according to Denis Sereno, who studies antimony-resistant Leishmania parasites at the Research Institute for Development (IRD), in Montpellier, France. He notes that arsenic levels in the drinking water of the 110 patients during 2006–10, when the treatment failures occurred, were not measured. The conclusions are based only on the correlation between outcomes and arsenic levels when the retrospective analysis was conducted, in 2012.

For this reason, further investigation into parasite resistance is needed, Sereno says. Even so, the findings are particularly interesting for sleeping sickness, a parasitic disease treated with melarsoprol, an arsenic-containing drug, he adds. If arsenic in drinking water can induce resistance to a drug containing the chemically similar antimony, he explains, the effect might be even more pronounced for a therapeutic agent containing arsenic itself.

Biplab Das is a freelance science writer based in India.