Determining the mechanisms of praziquantel resistance in schistosomiasis: insights and future directions

Schistosomiasis, a significant neglected tropical disease (NTD), poses a considerable public health challenge worldwide, particularly in sub-Saharan Africa. The current standard treatment used to treat human schistosomiasis is praziquantel (PZQ). Here we review and examine the mechanisms of action of the almost exclusive drug currently used to treat human schistosomiasis on a large scale, PZQ. It also discusses potential resistance mechanisms and the history of small molecule anti-schistosomal medication discovery over the past century. Despite more than 20 years of mass drug administration and preventive chemotherapy aimed at school-aged children, the disease burden continues to be significant in many areas. The World Health Organization program distributes up to 250 million PZQ tablets annually. Additionally, this review highlights the absence of new drugs or vaccines for this disease. Since the approval of PZQ in 1977, there has been a troubling scarcity of new therapeutic options or vaccines for schistosomiasis, raising concerns about a perceived stagnation in antischistosomal research. Here, we review discuss the current understanding of PZQ mechanisms of action and resistance. Moreover, it highlights the pressing need for new drug development and examines potential pharmacological alternatives globally. It advocates for more integrated control strategies for schistosomiasis, aiming to motivate medicinal chemists in endemic regions and elsewhere to intensify their research initiatives. Recommendations for advancing this field include increasing investment in research, fostering interdisciplinary collaboration, exploring alternative therapeutic strategies, supporting data-sharing initiatives, and raising awareness about the critical need for new treatments.