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Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

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dc.contributor.authorSundaraneedi, M.
dc.contributor.authorTedla, B.
dc.contributor.authorEichenberger, R.
dc.contributor.authorBecker, L.
dc.contributor.authorPickering, D.
dc.contributor.authorSmout, M.
dc.contributor.authorRajan, S.
dc.contributor.authorWangchuk, P.
dc.contributor.authorKeene, F.
dc.contributor.authorLoukas, A.
dc.contributor.authorCollins, J.
dc.contributor.authorPearson, M.
dc.contributor.editorGreenberg, R.M.
dc.date.issued2017
dc.description.abstractBackground: Schistosomiasis affects over 200 million people and there are concerns whether the current chemotherapeutic control strategy (periodic mass drug administration with praziquantel (PZQ)—the only licenced anti-schistosome compound) is sustainable, necessitating the development of new drugs. Methodology/Principal findings: We investigated the anti-schistosome efficacy of polypyridylruthenium(II) complexes and showed they were active against all intra-mammalian stages of S. mansoni. Two compounds, Rubb12-tri and Rubb7-tnl, which were among the most potent in their ability to kill schistosomula and adult worms and inhibit egg hatching in vitro, were assessed for their efficacy in a mouse model of schistosomiasis using 5 consecutive daily i.v. doses of 2 mg/kg (Rubb12-tri) and 10 mg/kg (Rubb7-tnl). Mice treated with Rubb12-tri showed an average 42% reduction (P = 0.009), over two independent trials, in adult worm burden. Liver egg burdens were not significantly decreased in either drug-treated group but ova from both of these groups showed significant decreases in hatching ability (Rubb12-tri—68%, Rubb7-tnl—56%) and were significantly morphologically altered (Rubb12-tri—62% abnormal, Rubb7-tnl—35% abnormal). We hypothesize that the drugs exerted their activity, at least partially, through inhibition of both neuronal and tegumental acetylcholinesterases (AChEs), as worms treated in vitro showed significant decreases in activity of these enzymes. Further, treated parasites exhibited a significantly decreased ability to uptake glucose, significantly depleted glycogen stores and withered tubercules (a site of glycogen storage), implying drug-mediated interference in this nutrient acquisition pathway. Conclusions/Significance: Our data provide compelling evidence that ruthenium complexes are effective against all intra-mammalian stages of schistosomes, including schistosomula (refractory to PZQ) and eggs (agents of disease transmissibility). Further, the results of this study suggest that schistosome AChE is a target of ruthenium drugs, a finding that can inform modification of current compounds to identify analogues which are even more effective and selective against schistosomes. Author summary: Schistosomiasis is a neglected tropical disease which affects over 200 million people and there is only one licensed drug, praziquantel, currently available for treatment. In a search for new drugs to control schistosomiasis, we tested the anti-schistosome efficacy of a series of ruthenium compounds and found that a number of them were able to inhibit parasite eggs from hatching and kill adult worms and praziquantel-refractory juvenile worms in vitro. We demonstrated that the compounds inhibit schistosome acetylcholinesterase (the enzyme that breaks down the neurotransmitter acetylcholine), which could potentially result in paralysis of the parasite, likely due to uncontrolled neuromuscular function caused by acetylcholine excess. Moreover, we showed that drug-treated worms had a significantly reduced ability to uptake exogenous glucose and markedly depleted glycogen stores, presumably through inhibition of the acetylcholinesterase-mediated glucose scavenging pathway. Lastly, we found that two of the drugs—Rubb12-tri and Rubb7-tnl—when used to treat schistosome-infected mice, were able to reduce worm burdens and significantly affect the viability of parasite eggs in vivo, which would have a marked impact on disease transmission. We believe that these complexes are desirable drug lead scaffolds which could be used to develop effective and selective compounds to control and treat schistosomiasis and, potentially, other parasitic diseases.
dc.description.statementofresponsibilityMadhu K. Sundaraneedi, Bemnet A. Tedla, Ramon M. Eichenberger, Luke Becker, Darren Pickering, Michael J. Smout, Siji Rajan, Phurpa Wangchuk, F. Richard Keene, Alex Loukas, J. Grant Collins, Mark S. Pearson
dc.identifier.citationPLoS Neglected Tropical Diseases, 2017; 11(12):e0006134-1-e0006134-21
dc.identifier.doi10.1371/journal.pntd.0006134
dc.identifier.issn1935-2727
dc.identifier.issn1935-2735
dc.identifier.orcidKeene, F. [0000-0001-7759-0465]
dc.identifier.urihttp://hdl.handle.net/2440/111286
dc.language.isoen
dc.publisherPublic Library Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1132975
dc.rights© 2017 Sundaraneedi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pntd.0006134
dc.subjectAnimals
dc.subjectMice
dc.subjectSchistosoma haematobium
dc.subjectSchistosoma mansoni
dc.subjectSchistosomiasis haematobia
dc.subjectSchistosomiasis mansoni
dc.subjectDisease Models, Animal
dc.subjectRuthenium
dc.subjectOrganometallic Compounds
dc.subjectPraziquantel
dc.subjectAcetylcholinesterase
dc.subjectGlucose
dc.subjectCholinesterase Inhibitors
dc.subjectBiological Transport
dc.subjectLarva
dc.subjectFemale
dc.subjectMale
dc.titlePolypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases
dc.typeJournal article
pubs.publication-statusPublished

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