Introduction
Schistosomiasis is one of the most prevalent parasitic diseases worldwide, affecting millions of people, especially in tropical regions. Standard treatment involves the use of praziquantel (PZQ), an effective anthelmintic. However, the emergence of PZQ-resistant Schistosoma mansoni strains has been reported, raising concerns about potential therapeutic failure. Studies indicate that resistance mechanisms may involve efflux pumps belonging to the ABC (ATP-binding cassette) family of transporters, such as P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRP). This study investigated the relationship between the activity of these pumps and PZQ resistance in S. mansoni.
Materials and methods
The study used a strain of S. mansoni obtained by continuous selective pressure of PZQ, resistant to doses of up to 1200 mg/kg in CD1 mice, and compared it to a susceptible strain. Ethidium bromide (EtBr) efflux assays and ex vivo PZQ susceptibility assays were performed, with and without the addition of verapamil, an efflux pump inhibitor. The expression of the SmMDR2 gene, an ortholog of Pgp in S. mansoni, was quantified by RT-qPCR.
Results
The results indicated that the resistant strain presented higher EtBr efflux activity compared to the susceptible strain, suggesting an increase in the expression of ABC transporters. Inhibition of these pumps by verapamil led to a significant accumulation of EtBr, indicating that resistant parasites have greater efficiency in the removal of toxic compounds. Furthermore, ex vivo assays demonstrated that coadministration of PZQ and verapamil significantly reduced the lethal concentration of PZQ in the resistant strain, partially restoring its efficacy. RT-qPCR analysis confirmed an overexpression of the SmMDR2 gene in the resistant strain, reinforcing its role in PZQ resistance.
Discussion
The findings of this study suggest that Pgp-type transporters, such as SmMDR2, play a crucial role in PZQ resistance in S. mansoni by reducing its intracellular bioavailability. Inhibition of these pumps by verapamil or other Pgp modulators may represent a viable therapeutic strategy for the management of PZQ resistance. These results are consistent with previous studies indicating the involvement of ABC transporters in drug resistance in helminths and other organisms.
Conclusion
SmMDR2 overexpression and increased efflux activity are hallmarks of PZQ resistance in S. mansoni. The combined use of PZQ with efflux inhibitors, such as verapamil, may represent a promising approach to restore treatment efficacy. Continuous surveillance of PZQ resistance is essential for effective control of schistosomiasis.
Reference :
PINTO-ALMEIDA, António et al. The Role of Efflux Pumps in Schistosoma mansoni Praziquantel Resistant Phenotype. PLoS ONE, v. 10, n. 10, p. e0140147, 2015. Available at: https://doi.org/10.1371/journal.pone.0140147. Accessed on: [access date].
