Drug resistance in Schistosomiasis: a review

Bruce, J. I.; Dias, L. C. S.; Liang, You-Sheng; Coles, G.C.

doi:10.1590/s0074-02761987000800025

Cited by 20 publications

(12 citation statements)

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“…We also found four main sensitive strains. At least four other strains (either resistant or sensitive) were punctually used and will not be discussed here (Bruce et al, 1987; Drescher et al, 1993; Pica-Mattoccia et al, 1993). …”

Section: Discussionmentioning

confidence: 99%

“…Many of them were abandoned due to low treatment efficiency, as well as toxic and sometimes mutagenic side effects to the human host (Galdino da Rocha Pitta et al, 2013). Another major concern regarding schistomicides is the rapid appearance of resistances, both in laboratory strains and natural populations of the parasite (Bruce et al, 1987; Coles et al, 1987; Drescher et al, 1993; WHO, 1998). Please note that to avoid any language confusion, we use here the definitions of drug resistance and tolerance in schistosomes as given by Coles (2002), with the former being “ when any isolate has a significantly lower cure rate than the most sensitive isolate ” and the later when the whole species is non-responsive to the drug.…”

Section: Introductionmentioning

confidence: 99%

“…First evidences of resistant worms to this molecule were published in the early 1970's (Rogers and Bueding, 1971). It was later demonstrated several times that schistosomes were in general cross-resistant or cross-susceptible to both hycanthone and another schistosomicide, oxamniquine (Jansma et al, 1977; Cioli and Pica-Mattoccia, 1984; Dias and Olivier, 1985; Bruce et al, 1987). Oxamniquine was often used as a proxy for hycanthone, as the later is not commercially produced anymore and was toxic to the host to a certain degree.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Since in hamster model, OZ78 shows similar efficacy against adult S. mansoni and S. japonicum, the different efficacy of the same drug against the two species of schistosomes in mice model might be associated to the different mouse strains used in experimental chemotherapy, particularly, the difference of immunological response between the two mouse strains, which remains to be further elucidated. On the other hand, it has been reported that the susceptibility of various geographical strains of S. mansoni to oxamniquine is different (Foster and Cheetham 1973;Bruce et al 1987;Delgado et al 1992;Abdul-Ghani et al 2009). Particularly, there had been a naturally resistant strain of S. mansoni which is able to survive drug doses 1,000-fold higher than the effective dose against sensitive parasites (Abdul-Ghani et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of synthetic trioxolane OZ78 against Schistosoma japonicum in mice and rabbits

et al. 2011

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Antischistosomal activities of a synthetic peroxide OZ78 (an ozonide carboxylic acid) against Schistosoma japonicum have been studied in mice and rabbits. Among 132 mice used, 30 of them were infected with 80-100 S. japonicum cercariae for collection of juvenile and adult schistosomes applied in in vitro tests. The remaining 102 mice were infected with 40 schistosome cercariae used for experimental treatment. Other 13 rabbits infected each with 200 schistosome cercariae were treated orally with OZ78 42 days post-infection. Most treated mice and rabbits were sacrificed 4 weeks post-treatment to collect residual schistosomes for evaluation of the drug efficacy. OZ78 and its sodium salt (OZ78-Na salt) 10-60 μg/mL alone exhibited no in vitro effect against day 14, day 21 schistosomula, and day 35 adult schistosomes. But OZ78 and OZ78-Na salt 10 and 20 μg/mL together with hemin 80 μg/mL showed decrease in worm motor activity and severe damage to the worm tegument and intestine, and all worms died within 3 days post-incubation. After infected mice were treated orally with OZ78 at a single dose of 400 mg/kg for 1 day, 34.9% of the worms shifted to the liver. Three and 7 days post-treatment, 100% of the worms were recovered from the liver. Fourteen days post-treatment, 92.3% of the worms still remained in the liver and 7.7% of the worms returned back to the mesenteric veins. Male and female worms shifted to the liver revealed in apparent shrinkage, degeneration of worm body, depigmentation in gut, and disappearance of ova in the uterus of some female worms. Meanwhile, dead worm and dead worm fragments were found in the liver tissues. In mice infected with various stages of schistosomes and treated orally with single OZ78 400 mg/kg, moderate or potential effect of the drug against day 0 (3-h-old worm), day 7, day 14, and day 21 juvenile worms and day 28, day 35 as well as day 42 adult worms were observed, the differences of total or female worm burdens between each treated group and control group were statistically significant (P < 0.01 or P < 0.05). Among the various stages of juveniles, day 7 worms were more susceptible to OZ78 with worm reduction of 83.8%, while the effect of OZ78 against day 28 to day 42 adult worms were similar. Finally, rabbits infected with adult schistosomes and treated with OZ78 at a single dose of 45 mg/kg or a daily dose of 35 mg/kg for three consecutive days resulted in significantly lower total and female worm burdens in comparison with that of control (P < 0.05) with total and female worm reductions of 84.1% and 84.7% as well as 74.3% and 77.4%, respectively. The results demonstrate that OZ78 possesses effect against both juvenile and adult S. japonicum in mouse model, and also shows effect against adult schistosomes in rabbits.

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“…Despite its high efficacy and low cost, the mass administration and reliance on a single drug increases the risk of the development of drug resistance. In fact, cases of significantly reduced susceptibility to PZQ have already been reported in field and laboratory isolates [2–4]. Hence, drug discovery in schistosomiasis is still of great relevance, and robust high throughput parasite screening techniques are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

A high-throughput colorimetric assay for detection of Schistosoma mansoni viability based on the tetrazolium salt XTT

et al. 2017

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Background Schistosoma mansoni is a trematode parasite that causes schistosomiasis, one of the most prevalent neglected tropical diseases, leading to the loss of 2.6 million disability-adjusted life years. Praziquantel is the only drug available, and new drugs are required. The most common strategy in schistosomiasis drug discovery is the use of the schistosomula larval-stage for a pre-screen in drug sensitivity assays. However, assessing schistosomula viability by microscopy has always been a limitation to the throughput of such assays. Hence, the development of validated, robust high-throughput in vitro assays for Schistosoma with simple readouts is needed. Here, we present a simple and affordable alternative to assess schistosomula viability. The method employed is based on the hydrosoluble tetrazolium salt XTT which has been widely used in other organisms but has never been used to drug screen in schistosomes.ResultsWe showed that schistosomula reduce XTT salt to a coloured formazan product and that absorbance levels reflected the viability and parasites number. This XTT viability assay was validated for high throughput screening of compounds in schistosomula, and dose-response curves of compounds could be reproduced.ConclusionsWe conclude that the XTT viability assay could be applied for the screening of large compounds collections in S. mansoni and accelerate the identification of novel antischistosomal compounds.

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Drug resistance in Schistosomiasis: a review

Cited by 20 publications

References 0 publications

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

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

Effectiveness of synthetic trioxolane OZ78 against Schistosoma japonicum in mice and rabbits

A high-throughput colorimetric assay for detection of Schistosoma mansoni viability based on the tetrazolium salt XTT

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