International Journal for Parasitology: Drugs and Drug Resistance最新文献

{"title":"Validation of solvent proteome profiling for antimalarial drug target deconvolution","authors":"Yijia Ji ,&nbsp;Joshua P. Morrow ,&nbsp;Christopher A. MacRaild ,&nbsp;Haijian Zhang ,&nbsp;Carlo Giannangelo ,&nbsp;Ralf B. Schittenhelm ,&nbsp;Darren J. Creek ,&nbsp;Ghizal Siddiqui","doi":"10.1016/j.ijpddr.2025.100626","DOIUrl":"10.1016/j.ijpddr.2025.100626","url":null,"abstract":"<div><div>Malaria remains a global health threat, with rising drug resistance accelerating the urgent need for new therapeutics. Target elucidation is a critical step in antimalarial drug discovery, enabling a deeper understanding of the molecular mechanisms of action of both existing and novel compounds. This study validates solvent-induced proteome profiling (SPP) as a proteomics-based approach for identifying drug-protein interactions in <em>Plasmodium falciparum</em>. SPP detects shifts in protein stability induced by ligand binding, allowing the identification of drug target/s without the need for compound modifications. Here, we successfully generated solvent denaturation curves for the <em>P. falciparum</em> proteome, and demonstrated the utility of SPP with five antimalarial compounds: pyrimethamine, atovaquone, cipargamin, MMV1557817 and OSM-S-106. In addition to measuring each compound's impact across the full denaturation curve, investigating protein levels at individual solvent percentages preserved specific stability changes that would otherwise be masked in pooled analyses performed by integral SPP. This strategy was critical for the identification of the cipargamin target, non-SERCA-type Ca²⁺-transporting P-ATPase (<em>Pf</em>ATP4). Notably, we propose live-cell treatment SPP as a novel approach, demonstrating its ability to identify the validated target of pyrimethamine, bifunctional dihydrofolate reductase-thymidylate synthase (<em>Pf</em>DHFR), with high specificity. We also introduced the novel one-pot mixed-drug SPP, which enables the evaluation of multiple drugs within a single lysate and experimental setup. This alternative method simplifies the experimental workflow and includes positive controls to affirm the performance of the experiment. Overall, this study demonstrates that SPP can be successfully applied in both lysate and live-cell treatment conditions to elucidate drug targets in <em>P. falciparum,</em> as well as providing additional information regarding the mechanisms of drug action, offering insights for the optimisation of existing antimalarials and the development of novel therapies.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100626"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surveillance of single nucleotide polymorphisms correlated to macrocyclic lactone resistance in Dirofilaria immitis from client-owned dogs across the United States.","authors":"Emily Curry, David Tack, Jessica Rodriguez, Danielle Brehm-Lowe, John Letherer, Megan Lineberry, Roger Prichard, Tobias Clark","doi":"10.1016/j.ijpddr.2025.100604","DOIUrl":"10.1016/j.ijpddr.2025.100604","url":null,"abstract":"<p><p>Dirofilaria immitis is a parasitic filarial nematode and the causative agent of heartworm disease in canids and other species. Heartworm disease is predominantly managed via macrocyclic lactone (ML) - based chemoprophylactics. Through opportunistic sampling, genotypically and phenotypically confirmed ML-resistant D. immitis isolates have been isolated in the Lower Mississippi River Valley region (LMRV); however, the pervasiveness of resistant isolates in the USA has not been evaluated. This study aimed to evaluate the geographic distribution and prevalence of genotypically ML-resistant heartworms in client-owned dogs across the USA over a 3-year period. Owner consent was obtained to collect microfilaremic blood samples from heartworm-positive dogs from participating clinics. Veterinarians completed a questionnaire on the known history of each dog, including treatment and travel history. A total of 310 microfilaremic blood samples were collected from 45 geographically diverse veterinary clinics located in 22 states. Microfilariae were filtered from blood, DNA extracted utilizing the QIAGEN QIAamp DNA Micro Kit and samples sequenced by the Génome Québec Innovation Centre to determine allele frequencies at nine SNP sites previously correlated with ML resistance. The highly predictive 2-SNP model was used to identify genotypically susceptible, mixed, and resistant populations. Computational analysis indicated 111 (35.8 %) were genotypically susceptible, 96 (31.0 %) were genotypically resistant, and 103 (33.2 %) were genotypically mixed. The genotypically mixed and ML-resistant infections were located within and outside of the endemic LMRV, as far north as Michigan, which indicates canine populations outside of the LMRV are at increased risk for transmission of potentially ML-resistant heartworm infections than previously hypothesized. Veterinary practitioners across the USA need to be aware of the potential risks of ML resistance heartworm infections and ensure patient compliance with recommended prevention protocols.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"100604"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel heterospirocyclic antimalarials with activity against artemisinin- and multidrug-resistant P. falciparum malaria","authors":"Liana Theodoridis ,&nbsp;Carlo Giannangelo ,&nbsp;Farrah El-Saafin ,&nbsp;MR Ranga Prabhath ,&nbsp;Christopher A. Macraild ,&nbsp;Pallavi Sharma ,&nbsp;Delphine Merino ,&nbsp;Darren J. Creek ,&nbsp;Teresa G. Carvalho","doi":"10.1016/j.ijpddr.2025.100627","DOIUrl":"10.1016/j.ijpddr.2025.100627","url":null,"abstract":"<div><div>Malaria is an infectious disease that imposes a significant global health burden. Increasing drug resistance creates an urgent demand for novel treatment options. We have previously synthesised a new class of heterospirocyclic compounds with novel chemical linkages, which have shown preliminary antimalarial activity. Compounds 25 and 26 display antimalarial activity within 24 h against a panel of drug-resistant strains of <em>Plasmodium falciparum</em>, the most virulent of human malaria parasites. Untargeted metabolomics analysis of <em>P. falciparum</em>-infected red blood cells revealed that the mechanism of action of compound 25 could involve disruption of the pyrimidine biosynthesis pathway and haemoglobin catabolism. Further, compounds 25 and 26 do not induce major toxicity in kidney- and hepatic-derived human cell lines, highlighting their specificity. These heterospirocyclic compounds represent a promising opportunity for antimalarial drug development and could prove relevant against drug-resistant malaria.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100627"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145722686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the inhibitory effects of emodin on Neospora caninum invasion and proliferation in vitro","authors":"Feixue Liu ,&nbsp;Jianhua Li ,&nbsp;Xin Li,&nbsp;Xu Zhang,&nbsp;Liuzhenxiu Yan,&nbsp;Lanbi Gao,&nbsp;Zhenzhen Liu,&nbsp;Pengtao Gong,&nbsp;Nan Zhang,&nbsp;Xichen Zhang,&nbsp;Xiaocen Wang","doi":"10.1016/j.ijpddr.2025.100624","DOIUrl":"10.1016/j.ijpddr.2025.100624","url":null,"abstract":"<div><div>The impact of neosporosis on the livestock industry has worsening each year. Globally, annual losses were estimated to exceed $2.4 billion, with abortion rates reaching up to 47 % in affected herds. But no effective vaccines or drugs are currently available for prevention and treatment. This study aimed to investigate the inhibitory effects of emodin on <em>Neospora caninum</em> (<em>N</em>. <em>caninum</em>) infection and its potential mechanisms. The appropriates safe concentration of emodin was determined by the Cell Counting Kit-8 (CCK-8) assay. The anti-<em>N. caninum</em> effects of emodin in Vero cells, MDBK cells, macrophages, as well as the combined effects of emodin and niclosamide in Vero cells, were further verified using qPCR or Giemsa staining. Subsequently, the effects of direct incubation of tachyzoites with emodin on <em>N. caninum</em> invasion and proliferation were also examined. The activation of necroptosis by emodin was evaluated by measuring Lactate Dehydrogenase (LDH) levels in the supernatant and assessing cellular pMLKL levels. The CCK-8 results indicated that emodin exhibited low toxicity to Vero cells, MDBK cells, and macrophages. The qPCR results showed that emodin reduced the number of <em>N. caninum</em> in Vero cells, MDBK cells, and macrophages. Giemsa results showed that the number of tachyzoites within the parasitophorous vacuole was decreased accordingly. Notably, emodin directly affected tachyzoites, reducing its invasion capability by 55 %–63 % and its proliferation capacity by 62 %–88 %. Additionally, the combination of emodin with niclosamide significantly enhanced its antiparasitic effects compared with emodin alone. Western blot analysis showed that emodin significantly increased pMLKL levels and enhanced LDH release, assisting <em>N. caninum</em> in activating necroptosis. However, the inhibitory effects of emodin on <em>N. caninum</em> invasion and proliferation were not significantly altered in <em>Mlkl</em>^{<em>−/−</em>} macrophages. In conclusion, emodin inhibited <em>N. caninum</em> infection may through a necroptosis-independent mechanism by directly targeting the parasite, highlighting its potential as a therapeutic candidate for neosporosis.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100624"},"PeriodicalIF":3.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative transcriptomics of naturally susceptible and resistant Trypanosoma cruzi strains in response to Benznidazole","authors":"Carlos Ospina ,&nbsp;Tatiana Cáceres ,&nbsp;Stivenn Gutiérrez ,&nbsp;Luz Helena Patiño ,&nbsp;Luis David Sáenz-Pérez ,&nbsp;Karen Moreno Medina ,&nbsp;Juan Carlos Villar ,&nbsp;Juan David Ramírez","doi":"10.1016/j.ijpddr.2025.100623","DOIUrl":"10.1016/j.ijpddr.2025.100623","url":null,"abstract":"<div><div>Chagas disease (CD), caused by the protozoan <em>Trypanosoma cruzi</em>, remains a major public health challenge due to limited treatment options, Benznidazole and Nifurtimox; which are associated with adverse effects and variable efficacy. The emergence of drug-resistant in <em>T. cruzi</em> strains, along with limited knowledge of the molecular mechanisms underlying resistance, hampers the development of more effective therapies. To explore these mechanisms, we performed a comparative transcriptomic analysis of two <em>T. cruzi</em> TcI strains: MG (naturally susceptible) and DA (naturally resistant) to Benznidazole. Parasites were cultured in LIT medium, and IC50 values were determined using the MTT assay. RNA was extracted and sequenced (RNA-seq), with reads aligned to a reference genome. Differential gene expressions were analyzed with DESeq2, functional enrichment through Gene Ontology (GO), and metabolic pathways were mapped via KAAS. The IC50 for Benznidazole in DA (28.92 μg/mL; 111.13 μM) was substantially higher than in MG (0.88 μg/mL; 3.39 μM), confirming differential susceptibility. DA showed 408 upregulated and 1515 downregulated genes, while MG had 153 upregulated and 866 downregulated (Log₂FoldChange ≥ 2 or ≤ −2). GO analysis indicated divergent biological processes between strains: DA exhibited enrichment in electron transport and detoxification, while MG was enriched in DNA repair and energy metabolism. Metabolic mapping revealed significant differences in the pentose phosphate pathway, glycolysis/gluconeogenesis, and the tricarboxylic acid (TCA) cycle. Key genes potentially involved in resistance like prostaglandin F2α synthase, trypanothione synthase, thioredoxin, and prostaglandin F synthase were identified as candidate therapeutic targets. These findings suggest that Benznidazole resistance in <em>T. cruzi</em> involves multifactorial, strain-specific responses at the transcriptomic and metabolic levels. By analyzing naturally resistant and susceptible TcI strains of <em>T. cruzi</em> under identical experimental conditions, this study reveals strain-specific transcriptomic adaptations that have not been previously characterized in naturally resistant and susceptible populations. These findings expand our current understanding of intrinsic Benznidazole resistance in <em>T. cruzi</em>, moving beyond purely experimental models. Specifically, they highlight novel metabolic and redox pathways that could serve as therapeutic targets effective against diverse <em>T. cruzi</em> strains and Discrete Typing Units (DTUs).</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100623"},"PeriodicalIF":3.4,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145415542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in intestinal helminth parasites of horses in the Asia-Pacific region: Current trends, challenges and future directions","authors":"Ghazanfar Abbas ,&nbsp;Martin K. Nielsen ,&nbsp;Charles E-Hage ,&nbsp;Abdul Ghafar ,&nbsp;Ian Beveridge ,&nbsp;Jenni Bauquier ,&nbsp;Anne Beasley ,&nbsp;Edwina J.A. Wilkes ,&nbsp;Peter Carrigan ,&nbsp;Lucy Cudmore ,&nbsp;Caroline Jacobson ,&nbsp;Kristopher J. Hughes ,&nbsp;Abdul Jabbar","doi":"10.1016/j.ijpddr.2025.100622","DOIUrl":"10.1016/j.ijpddr.2025.100622","url":null,"abstract":"<div><div>Over the past 25 years, significant progress has been made in understanding and managing equine gastrointestinal parasites in the Asia-Pacific region, particularly in Australia and New Zealand. This review synthesises current knowledge of the epidemiology, diagnostic methods, anthelmintic resistance (AR), and control strategies for major equine intestinal parasites, including cyathostomins, <em>Parascaris</em> spp., <em>Anoplocephala perfoliata</em>, and <em>Strongyloides westeri</em>. Recent studies highlight substantial regional variation in parasite prevalence, egg shedding and cyathostomin population composition, shaped by diverse climatic conditions. Of increasing concern is the emergence of resistance to commonly used anthelmintics which is now evident in both <em>Parascaris</em> and cyathostomins, although data for <em>S. westeri</em> and <em>A. perfoliata</em> remain limited. High-throughput molecular diagnostics, such as next-generation sequencing, have advanced species-level characterisation in Australia and Thailand. ELISA-based tests for <em>A. perfoliata</em> and encysted cyathostomins are promising but remain unvalidated and underutilised regionally. The routine use of combination anthelmintics, including benzimidazoles, praziquantel, pyrimidines, and macrocyclic lactones, may accelerate resistance across nematode and cestode populations, emphasising the need for regular efficacy monitoring and improved antiparasitic stewardship. Findings from recent research on horse parasites in Australia have informed the development of country's first national equine parasite control guidelines which recommend targeted or selective treatment strategies. However, the effectiveness of these strategies requires ongoing evaluation, particularly in year-round grazing systems in tropical and subtropical regions. Sustainable parasite control will depend on the integration of non-chemical strategies along with the use of anthelmintics and the establishment of a national parasite surveillance database. This review highlights the need for climate-specific treatment protocols, strengthened collaborative research infrastructure, and continued investment in innovative diagnostic and control methods to preserve equine health and anthelmintic efficacy across the region.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100622"},"PeriodicalIF":3.4,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a clinical risk scoring system for artesunate treatment failure prediction in malaria patients","authors":"Dasom Kim ,&nbsp;Da Hoon Lee ,&nbsp;Yubin Song ,&nbsp;Jung Sun Kim ,&nbsp;Hye Sun Gwak","doi":"10.1016/j.ijpddr.2025.100621","DOIUrl":"10.1016/j.ijpddr.2025.100621","url":null,"abstract":"<div><h3>Background</h3><div>Severe malaria remains a major cause of morbidity and mortality worldwide. Early identification of patients at high risk of poor response to treatment is essential, yet no simple clinical tool is currently available. This study aimed to develop a risk scoring system to predict failure to artesunate therapy.</div></div><div><h3>Methods</h3><div>This retrospective study included adult patients (aged ≥18 years) who received at least one dose of intravenous artesunate at the National Medical Center in South Korea between 2014 and 2023. Treatment failure (early or late clinical failure) was the response variable, which was defined according to WHO criteria. Candidate predictor variables included demographic, clinical, parasitological, and laboratory parameters. Odds ratios (ORs) and adjusted odds ratios (aORs) were calculated using univariate and multivariable logistic regression analyses, respectively. Final predictors were selected through backward elimination based on the Likelihood Ratio criterion, and a clinical risk scoring system was developed based on the adjusted ORs.</div></div><div><h3>Results</h3><div>Among 98 patients included in the final analysis, treatment failure occurred in 12 (12.2 %). Multivariable analysis identified female sex, parasitemia &gt;5 %, and impaired consciousness as independent risk factors. Using these variables, a risk-scoring system was constructed, and the predicted probabilities of treatment failure for patients with scores of 0, 1, 2, 3, and 4 points were 5 %, 16 %, 41 %, 72 %, and 90 %, respectively (AUROC = 0.768, 95 % CI: 0.605–0.931).</div></div><div><h3>Conclusions</h3><div>Parasitemia &gt;5 %, impaired consciousness, and female sex were predictive of artesunate treatment failure as defined by WHO clinical criteria. The developed risk scoring system provides a practical tool for identifying high-risk patients requiring intensified monitoring and alternative treatment strategies. These findings are derived from a South Korean cohort and should be interpreted with caution when extrapolated to endemic populations.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100621"},"PeriodicalIF":3.4,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Similar patterns of benzimidazole resistance alleles in ovine gastrointestinal nematodes from Western Canada and Eastern United States supports their shared origins and subsequent spread","authors":"Camila Queiroz ,&nbsp;Michel Levy ,&nbsp;Russell Avramenko ,&nbsp;Rebecca Chen ,&nbsp;Michaela Seal ,&nbsp;Elizabeth Redman ,&nbsp;Anne Zajac ,&nbsp;John Stuart Gilleard","doi":"10.1016/j.ijpddr.2025.100620","DOIUrl":"10.1016/j.ijpddr.2025.100620","url":null,"abstract":"<div><div>Livestock movement facilitates translocation of anthelmintic resistant parasites, but the extent to which resistance emergence depends on animal movement is still poorly understood. Benzimidazole resistance is widespread in ovine trichostrongylid nematodes, and our understanding of its molecular basis now allows for molecular epidemiology investigations. This study applies deep amplicon sequencing of the isotype-1 β-tubulin locus to compare the prevalence and frequency of benzimidazole resistance Single Nucleotide Polymorphisms (SNPs), and their alleles, for trichostrongylid populations from 102 Western Canadian and 28 Eastern USA sheep flocks. For <em>H. contortus</em>, benzimidazole resistance SNPs were at fixation tin almost all flocks from both regions; that is, present at, or close to, 100 % frequency. For <em>T. circumcincta</em> and <em>T. colubriformis</em>, although at fixation in most Eastern USA flocks, resistance SNPs they were at a much lower prevalence in Western Canada, consistent with the lower anthelmintic use and selection pressure. The benzimidazole resistance SNP profiles were identical across these regions: F200Y (TTC &gt; TAC) predominated for all three species in both regions, but there were differences between the species at codons 167 and 198. For <em>H. contortus</em>, F167Y (TTC &gt; TAC) was at moderate prevalence but no codon 198 resistance SNPs occurred in either region. For <em>T. circumcincta</em>, E198A (GAA &gt; GCA) was at low prevalence and for <em>T. colubriformis</em>, F200Y (TTC &gt; TAC) was the only resistance SNP detected in both regions. Analysis of diversity and distribution of Amplicon Sequence Variants (ASVs) carrying resistance SNPs revealed that, in all three species, the same major resistance alleles were present in both regions at very similar relative frequencies. These results are consistent with a model of benzimidazole resistant ovine gastrointestinal nematodes (GIN) spreading across North America from common origins facilitated by animal movement. This model emphasizes the importance of biosecurity in limiting the emergence and spread of anthelmintic resistance in ruminant GIN. Keywords: molecular epidemiology, deep amplicon sequencing, anthelmintic resistance, nemabiome, benzimidazoles.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100620"},"PeriodicalIF":3.4,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Illuminating the druggability of the Giardia duodenalis kinome through reannotation and high-throughput screens","authors":"Alexander Y.F. Lam ,&nbsp;Isabelle S. Lucet ,&nbsp;Aaron R. Jex ,&nbsp;Samantha J. Emery-Corbin","doi":"10.1016/j.ijpddr.2025.100619","DOIUrl":"10.1016/j.ijpddr.2025.100619","url":null,"abstract":"<div><div><em>Giardia duodenalis</em> (syn <em>Giardia intestinalis, Giardia lamblia</em>) is a neglected, microaerophilic gastrointestinal parasite reliant on broad spectrum anti-microaerophilic/-anaerobic nitroheterocyclic antibiotics (metronidazole) which have been in use for over 70 years. New drugs which avoid their predecessor’s shortfalls of toxic and adverse effects, as well as circumvent its increasing treatment failure, are urgently required to lower global rates of up to 200 million symptomatic cases annually. Kinases are essential regulatory enzymes that primarily catalyse the phosphorylation post-translational modification involved in dynamic cellular processes. Kinases are well-validated and attractive drug targets, with many kinase inhibitors demonstrating great success in the clinic as anticancer therapeutics. In <em>G. duodenalis</em>, its intriguing set of minimal “core” protein kinases and the highly expanded <em>Giardia</em>-specific Never-in-Mitosis-A related kinases (Neks) emerge as a novel druggable space. We propose this kinome as an understudied and underutilised space to explore novel antigiardial targets. Intriguingly, despite over 15 years of advances in kinase biology and new annotation tools, there are limited functional evidence on the existence of ‘Neks’ in <em>G. duodenalis</em>. To incentivise new efforts, we provide an updated kinome reannotation and examination of the giardial core and specific sub-kinomes using novel bioinformatic tools, suggesting a nomenclature and providing insights in a drug-discovery context. Lastly, we have conducted a high-throughput screening of 430 compounds, covering 53 kinase targets and 51 chemical scaffolds, identifying 83/430 antigiardial kinase inhibitors of which 33 true positives could be validated in a subset subjected to drug-susceptibility testing, highlighting intriguing spaces for further development and molecular probes to further explore kinase regulatory pathways in this parasite.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100619"},"PeriodicalIF":3.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges in applying W.A.A.V.P. criteria to diagnosing triclabendazole resistance in Fasciola hepatica, an example from the Southern Tablelands of New South Wales, Australia","authors":"Chelsie Uthayakumar ,&nbsp;Hayley Martinez DeCristi ,&nbsp;Emily Kate Francis ,&nbsp;Roger Alan Willoughby ,&nbsp;Shannon Taylor ,&nbsp;Nichola Eliza Davies Calvani","doi":"10.1016/j.ijpddr.2025.100618","DOIUrl":"10.1016/j.ijpddr.2025.100618","url":null,"abstract":"<div><div><em>Fasciola hepatica</em> (liver fluke) is a zoonotic parasite of global concern. In Australia, it is the 13th most important cause of economic loss in the sheep meat industry alone. Resistance to the frontline drug, triclabendazole (TCBZ), was first recorded in Australia in 1995 and has since emerged globally. In 2023, producers from the New South Wales (NSW) Southern Tablelands raised concerns over a reported 230% increase in liver fluke, which they suspected was due to drug resistance. To confirm or deny these suspicions, we co-designed a diagnostic field investigation aligned with guidelines from the World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) to evaluate the prevalence and susceptibility of <em>F. hepatica</em> on naturally infected sheep, cattle, and goat properties. Nine mobs (seven sheep, one goat, one cattle) across eight farms were divided into three treatment groups (15 animals/group) and treated with either TCBZ, closantel/abamectin (CLOS/AVM, positive control – sheep), albendazole (ABZ, positive control – goats), or water (H₂O; negative control). Prevalence was determined by sedimentation and faecal egg count (FEC), alongside a commercial coproantigen ELISA (cELISA) and in-house qPCR. Drug efficacy was assessed using faecal egg count reduction tests (FECRT) and coproantigen reduction tests (CRT). Four of the eight farms had a within-herd true prevalence &gt;25%. TCBZ resistance was confirmed on one sheep property (86–89% efficacy). The goat property demonstrated susceptibility to TCBZ (97–98% efficacy), but reduced efficacy of ABZ (79%), representing the first potential report of ABZ resistance in <em>F. hepatica</em> infecting goats. Nemabiome sequencing of co-infecting gastrointestinal nematodes confirmed widespread benzimidazole resistance, underscoring the broader challenges faced by producers. Other potential causes of drug failure included climate variability, pseudo-parasites, and low cELISA diagnostic sensitivity. These results highlight the complexity of diagnosing and managing drug resistance in naturally infected populations and reinforce the need for <em>Fasciola</em>-specific W.A.A.V.P. guidelines.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100618"},"PeriodicalIF":3.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}