Drug effects on metabolic profiles of Schistosoma mansoni adult male parasites detected by 1H-NMR spectroscopy

Abstract

Schistosomiasis is one of the most devastating neglected tropical parasitic diseases caused by trematodes of the genus Schistosoma. Praziquantel (PZQ) is today the only drug used in humans and animals for the treatment of schistosomiasis but unfortunately it is poorly effective on larval and juvenile stages of the parasite. Therefore, it is urgent the discovery of new drug targets and compounds. We have recently showed that the anti-anginal drug perhexiline maleate (PHX) is very active on multiple developmental stages of Schistosoma mansoni in vitro. It is well known that PHX impacts the lipid metabolism in mammals, but the final target on schistosomes still remains unknown. The aim of this study was to evaluate the ability of 1 H nuclear magnetic resonance (NMR) spectroscopy in revealing metabolic perturbations due to PHX treatment of S. mansoni adult male worms. The effects of PHX were compared with the ones induced by vehicle and gambogic acid, in order to detect different metabolic profiles and specificity of the PHX action. Remarkably a list of metabolites associated to PHX-treatment was identified with enrichment in several connected metabolic pathways including also the Kennedy pathway mediating the glycerophospholipid metabolism. Our study represents the first 1 H-NMR metabolomic approach to characterize the response of S. mansoni to drug treatment. The obtained "metabolic fingerprint" associated to PHX treatment could represent a strategy for displaying cellular metabolic changes for any given drug and to compare compounds targeting similar or distinct biochemical pathways.

Metabolomics reveal alterations in arachidonic acid metabolism in Schistosoma mekongi after exposure to praziquantel

“…Metabolomics is a powerful tool for identifying drug mechanism of action, which have been studied for many anthelminthic compounds targeting schistosomes, such as perhexiline maleate [ 19 ] and sclareol [ 31 ]. Moreover, this technique has been used to investigate drug resistance mechanisms and thus may lead to alternative treatments to combat the tolerance of pathogens.…”

“…Metabolomics, which is the global analysis of small molecule metabolites found in living organisms under certain conditions [ 18 , 19 ], is a powerful tool for identifying novel drug targets, biomarker discovery, the monitoring of disease, and studying disease pathogenesis, for example. [ 20 , 21 ].…”

“…studied the metabolomic profiles of the intracellular amastigote stage of Trypanosoma cruzi treated with six drugs and found that the tricarboxylic acid cycle was the most prominently affected pathway [ 18 ]. In the development of drugs against Schistosoma spp ., metabolomics has only been applied to study perhexiline maleate [ 19 ], and no data are available on the metabolic changes after PZQ treatment in this schistosomal parasite. Therefore, using metabolomic methodology and in-depth pathway analysis may improve our understanding of PZQ modes of action.…”

Untargeted serum metabolomic profiling for early detection of Schistosoma mekongi infection in mouse model

“…Metabolomics is the qualitative and quantitative study of small molecules in biological samples ( Fernández-García et al., 2018 ). It is widely used to study various aspects of schistosomiasis, for example, to elucidate the parasite’s response to drug treatments ( Guidi et al., 2020 ), or to identify new drug targets ( Chienwichai et al., 2021 ). Urine is an easily available and valuable body fluid for biomarker detection.…”

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part III: Helminths

“…In vitro studies showed that the anti-anginal drug, perhexiline maleate exhibited potent inhibitory activity against all developmental stages. When the investigators studied metabolomics, at baseline and after treatment, they identified that its mechanism of action is via inhibition of Kennedy pathway [3] .…”