Schistosome Drug Resistance

Bioorganometallic Compounds as Novel Drug Targets against Schistosomiasis in Sub-Saharan Africa: An alternative to Praziquantel?

“…Oxamniquine is an anti-schistosomal drug primarily used against schistosomiasis caused by the S. mansoni species only. 6 , 11 , 65 - 67 The tetrahydroquinoline compound 1 was produced in Germany and the United Kingdom during the 1940s and is among a series of related drugs, such as hycanthone, which were not marketable owing to issues such as toxicity or mutagenicity. 67 The ineffectiveness of the drug on S. haematobium and S. japonicum worms is a result of its mechanism of action, which requires the activity of sulfotransferase for conversion to its active form, an esterifying enzyme found only in the S. mansoni worm.…”

“… 6 , 11 , 65 - 67 The tetrahydroquinoline compound 1 was produced in Germany and the United Kingdom during the 1940s and is among a series of related drugs, such as hycanthone, which were not marketable owing to issues such as toxicity or mutagenicity. 67 The ineffectiveness of the drug on S. haematobium and S. japonicum worms is a result of its mechanism of action, which requires the activity of sulfotransferase for conversion to its active form, an esterifying enzyme found only in the S. mansoni worm. 11 , 65 , 67 Once in its active state as a sulfate ester, the ester dissociates in a non-enzymatic reaction to form electrophilic reactants capable of alkylating schistosomal DNA.…”

“… 67 The ineffectiveness of the drug on S. haematobium and S. japonicum worms is a result of its mechanism of action, which requires the activity of sulfotransferase for conversion to its active form, an esterifying enzyme found only in the S. mansoni worm. 11 , 65 , 67 Once in its active state as a sulfate ester, the ester dissociates in a non-enzymatic reaction to form electrophilic reactants capable of alkylating schistosomal DNA. This results in irreversible damage to nucleic acid metabolism, thereafter inhibiting protein synthesis and leading to a strikingly retarded death.…”

“… 1 The main contributing factors to PZQ being described as the best mono-therapeutic agent against schistosomiasis can be attributed to its inexpensiveness, safety, high efficacy, accessibility and effectiveness against all human schistosome species. 11 , 67 In addition, the drug only exhibits limited and mild side effects such as vomiting and diarrhea.…”

“… 66 Reviewing the evidence of the results from both experimental settings requires consideration of possible genetic, physiological and morphological markers to indicate possible resistance. 67 , 79 Studies that attempted experimental induction of PZQ resistance began in the 1970s and have continued to modern times with the use of lethal to sub-lethal doses of the drug, with great attention being paid to S. mansoni species. 78 , 79 Success in the selection of laboratory-induced PZQ-resistant S. mansoni worms was then reported in 1994 by Fallon and Doenhoff.…”