17 January 2022
Secrets behind resistance to schistosomiasis drug
Published online 24 December 2021
Study reveals how the parasitic worm can mutate to evade the main drug against schistosomiasis.
Insights into the mechanism of action of the only effective drug against schistosomiasis (bilharzia), could open new avenues to better treatments. The disease is caused by the water-borne parasitic worm Schistosoma mansoni. An international research team studied the effect of mutations in the gene coding for a protein channel in cell membranes in the worm. Variations in the gene sequence conferred varying levels of resistance against the drug prazinquantel (PZQ). Researchers at Qaboos University in Oman and the Oman Ministry of Health contributed samples of the parasite for the research.
Schistosomiasis is the world’s second-most devastating parasitic disease after malaria. The S. mansoni worm contaminates freshwater in the tropics and sub-tropics. It can spread through the human body to affect many organs, afflicting more than 200 million people worldwide and causing many deaths.
“A really nice feature of this project is that two groups working with two different approaches have highlighted the same gene,” says Timothy Anderson of Texas Biomedical Research Institute, USA.
Anderson’s group analysed many laboratory samples of S. mansoni to identify genetic differences responsible for the variable sensitivity of the worm to the PZQ drug. They found that some worms could survive high drug dosages due to mutations in the gene for the channel protein. Researchers led by Jonathan Marchant at the Medical College of Wisconsin, USA, also found evidence implicating the gene and its protein from pharmacological studies. The two groups collaborated on the new study. In addition to pinpointing the relevant gene and protein, they found that chemicals inhibiting or activating the protein can enhance or reduce drug resistance.
Explaining the potential of the findings, Winka Le Clec'h of the Anderson group says, “We could redesign PZQ to make a more efficient drug [and also] monitor the parasite for drug resistance mutations.” She adds that the team will now more fully examine sequence variation in the identified gene in natural populations of the parasite to clarify its significance in treatment failure.
Pharmacologist Timothy Geary of McGill University, Canada and Queen's University Belfast, UK, who was not involved in the study, hails it as “an impressive advance in our understanding of the pharmacology of praziquantel as a treatment for schistosomiasis”. He says this could help develop a molecular diagnostic procedure to monitor and combat the development of praziquantel resistance in the parasite. Geary emphasizes that resistance to PZQ is “a much feared threat” that could thwart efforts to eliminate schistosomiasis in regions where it is endemic.
Le Clec'h, W. et al. Genetic analysis of praziquantel response in schistosome parasites implicates a transient receptor potential channel. Sci. Transl. Med. 13, eabj9114 (2021).