Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms

Background: Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis. Methodology: We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay. Principal Findings: We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect. Conclusions: Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone. Author Summary: Schistosomiasis causes severe health problems in endemic areas of Africa, Southeast Asia, and Central and South America. Praziquantel is the drug of choice for treatment of at-risk populations; however, evolution of resistant worms under repeated treatment is of great concern. Combining praziquantel with another drug could not only increase efficacy of praziquantel, but also eventually hamper development of drug resistance. Our study reports the global praziquantel-induced transcriptional changes of Schistosoma mansoni adult worms in vitro, in the context of the mature female mating status (paired or unpaired). We identified sets of genes that were differentially affected in paired or unpaired mature females; we also identified genes that were similarly affected in males and females. Aiming to find possible new candidates to be tested as synergistic drugs, we used functional analysis of gene interaction networks to identify parasite genes whose expression was affected by praziquantel, and encode proteins whose human homologs are targets of different drugs already used to treat other diseases. This analysis suggested omeprazole, a widely prescribed drug, as a potential partner for praziquantel in a combination treatment. Finally, we demonstrated that this praziquantel-omeprazole combination resulted in increased worm lethality in vitro when compared with praziquantel or omeprazole alone.