What is the mechanism of action of praziquantel and how might resistance strike?

Abstract

Future Medicinal ChemistryVol. 7, No. 6 CommentaryFree AccessWhat is the mechanism of action of praziquantel and how might resistance strike?Pauline M Cupit & Charles CunninghamPauline M CupitSkaggs School of Pharmacy & Pharmaceutical Sciences, UC San Diego, La Jolla, CA 92093, USASearch for more papers by this author & Charles CunninghamAuthor for correspondence: E-mail Address: ccunnin@unm.eduDepartment of Biology, University of New Mexico, Albuquerque, NM 87103, USASearch for more papers by this authorPublished Online:21 May 2015https://doi.org/10.4155/fmc.15.11AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: drug resistancemechanism of actionpraziquantelschistosomesschistosomiasisSchistosomiasis, also known as bilharzia, is a neglected tropical disease affecting over 249 million people of which approximately 45% are school-aged children. Although there are significant numbers of people with the disease in Asia and South America, over 90% of those infected reside in Africa. The Global Burden of Disease Study 2010 estimated 11,700 deaths and 2,986,000 years lost to disability due to schistosomiasis in that year [1,2].In 2012, the World Health Organization produced a ‘roadmap’ whose ultimate goal was the “…elimination of NTDs or reductions in their impacts to levels at which they are no longer considered public-health problems” [3]. Schistosomiasis was listed as a disease for potential elimination in the Eastern Mediterranean, Caribbean, Indonesia and Mekong River basin by 2015 and Brazil by 2020. Understandably, a more conservative note was sounded for Sub-Saharan Africa where worry over availability of medication was cited as the reason for failing to schedule elimination by 2020. The best-case scenario that could be made was with widespread availability of medication and strong political support schistosomiasis could be “…eliminated as a ‘public health problem’ in multiple countries in Africa by 2020.”The causative agents of schistosomiasis are digenetic trematode worms belonging the genus Schistosoma with Schistosoma mansoni, S. japonicum and S. haematobium being responsible for the majority of cases. Unfortunately, there is no vaccine available for the treatment of human schistosomiasis nor is the development of one on the horizon. Praziquantel (PZQ) is the only widely available drug for treatment of the disease and is thus at the heart of all control programs. It has been available for over 30 years yet the mechanism by which it kills schistosomes remains unknown and worries persist over the potential for mass administration campaigns to eventually diminish its usefulness. Here, we provide an introduction to schistosomiasis and discuss our current understanding of the mechanism of action of PZQ and the potential for widespread drug resistance.BackgroundWhile S. mansoni and S. japonicum are associated with intestinal schistosomiasis where mature schistosomes relocate to the mesenteric veins from the liver, S. haematobium locate to the pelvic venous plexus and are associated with urogenital schistosomiasis. Longevity of infection combined with the presence of multiple egg-laying paired females in any one individual results in untreated patients carrying significant egg burdens and it is the eggs rather than the parasite that are responsible for many of the clinical problems associated with the disease [4].A number of agents have been employed to treat schistosomiasis. Some proved to have low efficacy while others such as antimony derivatives were overly toxic and discarded when more efficient drugs such as hycanthone and oxamniquine became available. These drugs were only effective against S. mansoni and were abandoned with the appearance of drug resistance in both laboratory and field populations and the development of a cheap, safe and effective alternative. In 1972, the anthelmintic activity of pyrazinoisoquinoline derivatives was discovered in the laboratories of Bayer AG and E. Merck and PZQ was developed subsequently as a new therapeutic with a broad spectrum of activity against both trematodes and cestodes. The first clinical trials were conducted in the late 1970s and the development of improved methodologies for synthesis of PZQ in 1983 ensured the availability of a cost-effective treatment for the disease.PZQ is generally administered at a dose of 40 mg/kg and the drug's effectiveness is usually assessed by determining S. mansoni or S. japonicum egg counts in fecal samples using Kato-Katz smears or through urine filtration and counting S. haematobium eggs. Kato-Katz smears are considered to be an insensitive tool that may underestimate egg burdens and overestimate cure rates. More recently a point-of-care circulating cathodic antigen cassette (POC-CCA) has become available for urine testing of S. mansoni infected individuals. As outlined below, however, this assay may also have problems regarding sensitivity.The outcome of many studies suggests the standard dose of PZQ will be effective in providing a cure in up to 90% of cases. For example, in a study of the efficacy of 40 mg/kg PZQ administered to 160 preschool-aged children (an often ignored population in chemotherapy control campaigns) in a S. mansoni and S. haematobium endemic region of Côte d’Ivoire there was a cure rate of 88.6% and an egg reduction rate of 97.7% against S. mansoni and cure and egg reduction rates of 88.9 and 98.0%, respectively, against S. haematobium [5]. The POC-CCA test suggested a much lower level of efficacy against S. mansoni in these young children with a cure rate of only 53.8% though this may reflect the ability of the test to detect urinary CCA in the immediate post-treatment follow-up period. Irrespective of the dose or diagnostic test used, PZQ rarely affects a 100% cure rate and while the drug has made significant inroads toward relieving the suffering associated with symptoms of schistosomiasis it has not proved a magic bullet for the disease. The major drawback is the drug is widely reported to be ineffective against sexually immature juvenile schistosomes in the 2–4 weeks following infection of the mammalian host [6]. Within the context of first world medicine this of course is not a problem as repeated treatment spaced over a number of weeks should kill all parasites once the patient has left the endemic area. For economically disadvantaged third world populations living in rural areas without access to proper sanitation or regular treatment, the drug serves to greatly ameliorate symptoms in the short term but does not act as a long-term solution.Severe side effects associated with treatment of patients with a relatively high level of infection have been observed but are often transient. In a cohort of patients heavily infected with S. mansoni, these included abdominal pain, diarrhea, bloody diarrhea, vomiting and to a lesser extent, pruritus and urticaria. With intestinal schistosomiasis, the severe symptoms have been linked to worm death in the mesenteric veins while allergic reactions are likely caused by the significant increase in circulating parasite antigens [7].A further problem with PZQ is the tablets themselves. Many of the ongoing attempts at schistosomiasis control are aimed at school-aged children who often have trouble swallowing the tablets because of their large size as well as finding them unpalatable due to their bitter taste. PZQ is manufactured and administered as a racemic mixture of (S)- and (R)-stereoisomers and while the anthelmintic properties of the drug are associated with (R)-PZQ the bitter taste lies predominantly with (S)-PZQ [8]. This has led to the obvious conclusion that administration of only (R)-PZQ might halve the necessary dose thus decreasing tablet size and greatly improve taste. Toward this goal, we [9] and others [10] have published viable methodologies that show great promise for laboratory or large-scale production of (R)-PZQ. Enantiopure (R)- and (S)-PZQ and their derivatives [9] should also prove useful in determining the mechanism of action of the drug.Mechanism of action of praziquantelAlthough PZQ has been the mainstay treatment for schistosomiasis for many years, its precise mechanism of action remains unknown. When schistosomes come in contact with PZQ in vitro, they immediately undergo a rapid influx of Ca2+ accompanied by an intense muscular paralysis. Another notable feature is vacuolation and blebbing of worm tegumental and subtegumental structures in adults but not juveniles [11]. This is thought to disrupt the tegument and expose parasite surface antigens leading to recognition and parasite clearance by the host immune system and may account indirectly for the difference in sensitivity between juvenile and mature stages.Whether these observable phenomena are intimately linked with, or are simply a secondary consequence of PZQ binding to its molecular target remains to be deduced. The notion that PZQ acts primarily through disruption of ion transport was given credence in a series of papers by Greenberg et al. (for a review see [12]). This work suggested PZQ alters the function of voltage-operated Ca2+ channels (VOCC) through a unique channel β subunit. Two distinct VOCC β subunits were identified in schistosomes. A conventional form homologous to that found in mammals and a second, variant form lacking two serine residues which formed consensus protein kinase C phosphorylation sites in the β interaction domain (BID) of the conventional molecule. At the time, the BID was thought to make contact with the pore forming α subunit and play a key role in channel control. Co-expression of the variant schistosome β subunit with a mammalian α1 subunit in Xenopus oocytes conferred PZQ sensitivity, measured by increased Ca2+ current, on the normally PZQ-insensitive α1 subunit, a response analogous to PZQ induced Ca2+ influx in schistosomes. When the two missing serine residues were mutated into the variable subunit it lost this ability and conversely, co-expression of the α1 subunit with a conserved β subunit with both serine residues mutated out conferred PZQ sensitivity. Crystal structures of mammalian VOCC have subsequently demonstrated that the BID domain does not make contact with the α subunit and is in fact buried in the β subunit [13] suggesting that mutation of the serine residues simply leads to a conformational change in the β subunit structure. Unfortunately, similar experiments could not be carried out using S. mansoni α1 subunits, as these have proved impossible to express with their function intact. In further support of the variant β subunit playing some role PZQ sensitivity is the observation that other member of the phylum Platyhelminthes including the cestode tapeworm Taenia solium, the trematode liver fluke Clonorchis sinensis and the free living planarian flatworm Dugesia japonica are susceptible to the drug and have the variable VOCC β subunit.Although these experiments and observations seem to indicate some role for the VOCC β subunits in the mode of action of PZQ, there has also been a note of doubt whether Ca2+ influx is central to the anthelmintic effect of PZQ. For example, PZQ-insensitive juveniles undergo muscular contraction and paralysis on exposure to the drug and Pica-Mattoccia and Cioli demonstrated a large uptake of Ca2+ by juvenile S. mansoni in the presence of the drug [14]. These results led Pica-Mattoccia and Cioli to conclude ‘calcium accumulation by itself, at least as measured by whole parasites maintained in vitro, may not represent an exhaustive explanation for the schistosomicidal effects of PZQ.’ In addition, the observation that the gene encoding the variable β subunit is expressed in juvenile schistosomes argues against differential expression of the β subunits being the defining factor in PZQ susceptibility [15].The belief that VOCC plays a role in conferring PZQ susceptibility has been supported further by the work of Marchant et al. on the effects of PZQ on tissue regeneration in D. japonica. When both the head and tail of this organism are amputated they successfully regrow while maintaining the anterior–posterior polarity of the original body plan. When the amputated worms are exposed to PZQ, a complete duplication of the entire anterior–posterior axis occurs during regeneration to yield two-headed organisms with duplicated, integrated central nervous and organ systems. Significantly, RNAi mediated knock down of genes encoding both the variable and conserved β subunits leads to the ablation of the PZQ invoked bipolarity [16]. In subsequent work, this group provided a detailed molecular characterization of D. japonica Ca2+ α subunits (Cav). Of the five Cav subunits identified, two L-type sequences Cav1A and Cav1B were investigated further using RNAi technology. Knock down of the gene encoding Cav1A led to a loss of the ability of PZQ to bipolarize the amputated worms. In contrast, when the gene encoding Cav1B was knocked down the number of bipolarized worms increased significantly beyond that observed in controls on exposure to PZQ [17]. PZQ stimulus of Ca2+ entry through Cav1A was also found to inhibit hedgehog signaling in a neuronally enriched fraction of cells and to be antagonized by Ca2+ influx through Cav1B. Thus, PZQ appears, at least in this model, to disrupt Ca2+ influx into neuronal cells through activation of Cav1A. How does PZQ induced disruption of anterior–posterior polarity in a free-living flatworm enhance our understanding of PZQ induced death in schistosomes? One suggestion is that the lack of a broad VOCC repertoire in schistosomes compared with flat worms results in a greater vulnerability to misregulated Cav1A in schistosomes with the influx of Ca2+ triggering not only muscle paralysis but also pathways leading to tegumental damage in adults but not juveniles [18].It has also been suggested that PZQ mediates its anthelmintic effects through binding to actin, myosin light chain, alteration of membrane fluidity, inhibiting phosphoinositide turnover, reducing schistosomal glutathione concentration or inhibiting nucleoside uptake but many of these hypotheses lack serious investigation beyond the initial report.Praziquantel resistanceAs PZQ is the only anthelmintic drug that is cheap, widely available and effective against all forms of schistosomiasis, it is understandable that there has long been concern its usefulness may be diminished or lost to resistance. Fortunately, it would appear that, until now, resistance has either been misattributed or if it was present, short lived. In 1995, Stelma et al. reported on treatment of a Senegalese population heavily infected with S. mansoni [7]. While there was a highly significant drop in egg numbers in 352 patients 12 weeks after PZQ treatment the cure rate was only 18%. Although the authors did consider PZQ resistance may have been one explanation for reduced efficacy of drug treatment, they also acknowledged what is now viewed as the more likely scenario; that both intensity of infection and timing of the follow-up period, which left adequate time for the development of PZQ-insensitive, prepatent infections, were more significant factors. Supporting this less worrisome outcome was the later observation that an isolate obtained from snails in the endemic area matured at a slower rate than established laboratory strains of S. mansoni [19]. Of more significance were eight isolates derived from Egyptian patients treated on three occasions with PZQ [20]. These isolates had significantly less sensitivity to PZQ than controls and several maintained reduced sensitivity after several passages through mice in the absence of PZQ, however, this came at the cost of diminished reproductive fitness [21]. This loss of fitness may account for the inability to find evidence of resistance after intense PZQ treatment of individuals in the same area of Egypt 10 years after the initial finding [22]. Melman et al. reported a link between reduced PZQ sensitivity of S. mansoni miracidia derived from Kenyan patients and increasing number of PZQ treatments [23]. Again, isolates derived from a patient who had undergone multiple PZQ treatments that showed significantly reduced susceptibility proved difficult to maintain in the laboratory beyond one or two generations.Several groups have induced PZQ resistance in the laboratory by maintaining schistosomes in mice over several generations under increasing sublethal and then previously lethal doses of PZQ [24]. The molecular mechanisms underpinning induced resistance remains unknown, however, as with field-derived strains with reduced sensitivity, these isolates also lack long-term stability and, in addition, show reduced genetic diversity [24]. Remarkably, Couto et al. were able to induce reduced sensitivity in one generation by feeding PZQ to the intermediate snail stage of the parasite though, again, the mechanism of selection has yet to be elucidated [25].What might the molecular mechanism of resistance in field and/or laboratory isolates be? One clue might be provided by investigations that suggest induction of ATP-binding cassette (ABC) proteins involved in the transport of toxins and xenobiotics may underpin natural juvenile resistance. Kasinathan and Greenberg demonstrated that juvenile worms express approximately 2.5-fold higher basal levels of two ABC transporter gene transcripts (encoding SmMRP1 and SMDR2) than adults [26] while Hines-Kay et al. showed significantly increased levels of transcripts encoding ABC transporters SMDR1, SmMRP1, SmMRP2 and SMDR3 in juveniles exposed to PZQ in vitro [27].ConclusionIn the absence of cheap, broad-spectrum alternative chemotherapeutics and with no indication that a vaccine is likely to become available soon, PZQ is likely to remain the drug of choice for treatment of schistosomiasis. We remain no closer to identifying the drug target or metabolic pathways that contribute to schistosome death. Understanding the precise mechanism of action of the drug will provide important insights in the search for new compounds that might complement PZQ either through targeting independent pathways or overcoming its lack of efficacy against juveniles.Why is PZQ resistance not more evident? The simplest answer may be schistosomes have not yet come under enough pressure to allow resistance to develop. Approximately 42 million people, representing less than 20% of infected individuals, were treated with PZQ in 2012 [28]. Most were school-aged children with preschool and adult populations often ignored. Even for those fortunate enough to receive treatment, it is often intermittent leaving a large refugium of drug sensitive parasites. Thus, a potential combination of the reduced fitness of drug resistant parasites and large refugium has likely combined to keep resistance at bay. As the World Health Organization ‘roadmap’ toward control of schistosomiasis by 2020 unfolds, the number of PZQ tablets dispensed will increase significantly in the coming years. Merck KgaA has made 250 million tablets freely available each year in the medium term and with other manufacturers expected to contribute to any shortfall the conditions for resistance developing will improve. It is ironic that it may be the aim of simply controlling rather than eradicating the disease that ultimately reduces the likelihood of this occurring.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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actionpraziquantelschistosomesschistosomiasisFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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