Enzymatic basis for the lack of oxamniquine activity in Schistosoma haematobium infections

Pica‐Mattoccia, Livia; Novi, A.; Cioli, Donato

doi:10.1007/s004360050320

Cited by 24 publications

(19 citation statements)

References 9 publications

(10 reference statements)

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“…Interestingly, we observed a good in vitro activity of metrifonate, a drug recommended for treating infections with S. haematobium , on S. mansoni NTS, which is in line with a previous study using adult worms [25]. Oxamniquine (used for the treatment of S. mansoni infections) showed moderate activity against S. haematobium and S. mansoni NTS, a finding, which is in contrast to previous results using in vitro cultures with adult worms [26]. S. haematobium adults were not affected by oxamniquine, while a moderate activity was observed against S. mansoni adult worms [15,26].…”

Section: Discussionsupporting

confidence: 88%

“…Oxamniquine (used for the treatment of S. mansoni infections) showed moderate activity against S. haematobium and S. mansoni NTS, a finding, which is in contrast to previous results using in vitro cultures with adult worms [26]. S. haematobium adults were not affected by oxamniquine, while a moderate activity was observed against S. mansoni adult worms [15,26]. These varying drug sensitivities between the schistosomular and adult stage might possibly be explained with differences in drug activating enzymes, the main target of oxamniquine [26].…”

Section: Discussioncontrasting

confidence: 85%

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Development of an in vitro drug screening assay using Schistosoma haematobium schistosomula

2012

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BackgroundThe development of novel antischistosomal drugs is crucial, as currently no vaccine and only a single drug is available for the treatment of schistosomiasis. Fast and accurate in vitro assays are urgently needed to identify new drug candidates and research efforts should include Schistosoma haematobium. The aim of the present study was to develop a S. haematobium drug sensitivity assay based on newly transformed schistosomula (NTS).MethodsWe first undertook comparative studies on the cercarial emergence rhythms of the intermediate host snails Biomphalaria glabrata (S. mansoni) and Bulinus truncatus (S. haematobium). Two transformation methods as well as three purification methods were studied on S. haematobium cercariae in order to produce a large number of viable and clean NTS. Known antischistosomal drugs were tested in the established NTS assay in vitro. Drug effects were evaluated either microscopically or fluorometrically, using a resazurin based viability marker. Microscopically obtained IC50 values were compared with results obtained for S. mansoni.ResultsA circadian rhythm existed in both snail species. Infected B. truncatus snails shed less cercariae than B. glabrata during the testing period. The highest transformation rate (69%) of S. haematobium cercariae into NTS was obtained with the vortex transformation (mechanical input) and the highest purification factor was observed using Percoll®. The fluorimetric readout based on resazurin was very precise in detecting dead or/and severely damaged schistosomula.ConclusionsWith the use of viability markers such as resazurin, drug screening assays using S. haematobium NTS can be efficiently performed. However, drugs acting on the morphology and motility of S. haematobium NTS, such as metrifonate are missed. Drug sensitivity assays with NTS of both species, S. haematobium and S. mansoni, showed very similar results using known antischistosomal drugs. The S. mansoni NTS assay might be more suitable as primary screen in drug discovery efforts, which ultimately aim for a broad-spectrum antischistosomal drug as a larger number of S. mansoni NTS can be generated.

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Section: Discussionsupporting

confidence: 88%

Section: Discussioncontrasting

confidence: 85%

Development of an in vitro drug screening assay using Schistosoma haematobium schistosomula

2012

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“…OXA kills S. mansoni but not the other human schistosome species S. haematobium and japonicum (10, 11). To investigate species-specific drug action, we conducted a phylogenetic analysis.…”

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confidence: 99%

“…Genetic complementation experiments demonstrate that the same gene determines resistance in both field and laboratory-selected parasites, although whether the same mutations are responsible is unknown (9). OXA is species-specific (10, 11), killing S. mansoni (67 million cases) but not other schistosome species ( S. haematobium , 119 million cases) in Africa or S. japonicum (1 million cases) in Asia (1). …”

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confidence: 99%

Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites

Valentim¹,

Cioli²,

Chevalier³

et al. 2013

Science

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147

232

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Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally-derived F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi knockdown and biochemical complementation assays and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide.

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“…In the same article, the authors established that adult male worms, that are more sensitive to the drugs than females, have a higher enzymatic activity than females and immature stages (mostly unaffected by the drugs at the classical therapeutic concentration, and having a very low enzymatic activity). A difference in the enzyme specificity might also explain why hycanthone, but not oxamniquine, is efficient against Schistosoma haematobium (Pica-Mattoccia et al, 1997). The sequencing of the genome of S. mansoni (Berriman et al, 2009) provided new opportunities of investigation, and Valentim et al (2013) recently used linkage mapping methods to identify the gene responsible for resistance in the HR and MAP strains.…”

Section: Introductionmentioning

confidence: 99%

Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni

et al. 2014

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Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing an important economic burden. The schistosomicides hycanthone, and its later proxy oxamniquine, were widely used for treatments in endemic areas during the twentieth century. Recently, the mechanism of action, as well as the genetic origin of a stably and Mendelian inherited resistance for both drugs was elucidated in two strains. However, several observations suggested early on that alternative mechanisms might exist, by which resistance could be induced for these two drugs in sensitive lines of schistosomes. This induced resistance appeared rapidly, within the first generation, but was metastable (not stably inherited). Epigenetic inheritance could explain such a phenomenon and we therefore re-analyzed the historical data with our current knowledge of epigenetics. In addition, we performed new experiments such as ChIP-seq on hycanthone treated worms. We found distinct chromatin structure changes between sensitive worms and induced resistant worms from the same strain. No specific pathway was discovered, but genes in which chromatin structure modifications were observed are mostly associated with transport and catabolism, which makes sense in the context of the elimination of the drug. Specific differences were observed in the repetitive compartment of the genome. We finally describe what types of experiments are needed to understand the complexity of heritability that can be based on genetic and/or epigenetic mechanisms for drug resistance in schistosomes.

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Enzymatic basis for the lack of oxamniquine activity in Schistosoma haematobium infections

Cited by 24 publications

References 9 publications

Development of an in vitro drug screening assay using Schistosoma haematobium schistosomula

Development of an in vitro drug screening assay using Schistosoma haematobium schistosomula

Genetic and Molecular Basis of Drug Resistance and Species-Specific Drug Action in Schistosome Parasites

Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni

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