Transcriptional phenotype of the anti-parasitic benzodiazepine meclonazepam on the blood fluke Schistosoma mansoni

TL;DR

This study explores meclonazepam, a benzodiazepine, as a potential new treatment for schistosomiasis, showing it kills parasites and causes gene changes distinct from the current drug praziquantel.

Contribution

The study reveals the transcriptional effects of meclonazepam on Schistosoma mansoni and confirms its efficacy against both drug-susceptible and resistant parasites.

Findings

Meclonazepam causes tegument damage and activates pro-apoptotic caspases, indicating parasite death.

In vivo meclonazepam exposure alters gene expression of many flatworm-specific transcripts and genes related to host interaction.

Meclonazepam is effective against both praziquantel-susceptible and resistant schistosome populations.

Abstract

There are limited control measures for the disease schistosomiasis, despite the fact that infection with parasitic blood flukes affects hundreds of millions of people worldwide. The current treatment, praziquantel, has been in use since the 1980’s and there is a concern that drug resistance may emerge with continued monotherapy. Given the need for additional antischistosomal drugs, we have re-visited an old lead, meclonazepam. In comparison to praziquantel, there has been relatively little work on its antiparasitic mechanism. Recent findings indicate that praziquantel and meclonazepam act through distinct receptors, making benzodiazepines a promising chemical series for further exploration. Previous work has profiled the transcriptional changes evoked by praziquantel treatment. Here, we examine in detail schistosome phenotypes evoked by in vitro and in vivo meclonazepam treatment. These data confirm that meclonazepam causes extensive tegument damage and directly kills parasites, as measured by pro-apoptotic caspase activation. In vivo meclonazepam exposure results in differential expression of many genes that are divergent in parasitic flatworms, as well as several gene products implicated in blood feeding and regulation of hemostasis in other parasites. Many of these transcripts are also differentially expressed with praziquantel exposure, which may reflect a common schistosome response to the two drugs. However, despite these similarities in drug response, praziquantel-resistant parasites retain susceptibility to meclonazepam’s schistocidal effects. These data provide new insight into the mechanism of antischistosomal benzodiazepines, resolving similarities and differences with the current frontline therapy, praziquantel.

Schistosomiasis, a neglected tropical disease caused by parasitic flatworms, affects hundreds of millions of people worldwide. The drug praziquantel is the frontline treatment for this disease, but alternative therapies are needed to address the potential emergence of drug resistance. In this study, we revisit an old antischistosomal compound, meclonazepam, which belongs to a chemical series (benzodiazepines) which have promise for further development as schistosomiasis therapies. Following meclonazepam treatment we were able to observe biochemical readouts of worm death (pro-apoptotic caspase activation), indicating effective schistocidal activity. Drug-evoked changes in gene expression were then measured, showing that many transcripts affected by meclonazepam exposure are unique to parasitic flatworms. Many gene products with differential expression also have putative direct or indirect interactions with the host immune system. Finally, we tested meclonazepam’s ability to kill both praziquantel-susceptible and praziquantel-resistant populations of schistosomes. The drug was equally effective at killing both groups of parasites, suggesting that benzodiazepines could be developed as valuable alternative therapies in the fight against schistosomiasis.

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