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

{"title":"Development of a clinical risk scoring system for artesunate treatment failure prediction in malaria patients.","authors":"Dasom Kim, Da Hoon Lee, Yubin Song, Jung Sun Kim, Hye Sun Gwak","doi":"10.1016/j.ijpddr.2025.100621","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2025.100621","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Among 98 patients included in the final analysis, treatment failure occurred in 12 (12.2 %). Multivariable analysis identified female sex, parasitemia >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).</p><p><strong>Conclusions: </strong>Parasitemia >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.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"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}

{"title":"Biological and molecular characterisation of in vitro selected miltefosine-resistant Leishmania amazonensis lines","authors":"Laura Fernanda Neira ,&nbsp;Héllida Marina Costa-Silva ,&nbsp;Juliana Martins Ribeiro ,&nbsp;Silvane Maria Fonseca Murta ,&nbsp;Patricia Escobar","doi":"10.1016/j.ijpddr.2025.100617","DOIUrl":"10.1016/j.ijpddr.2025.100617","url":null,"abstract":"<div><div>Miltefosine (MTF) is currently the only available oral treatment for leishmaniasis. However, increasing reports of therapeutic failure have raised concerns about emerging resistance. This study aimed to investigate the effects of reduced MTF susceptibility loss in the protozoan parasite <em>Leishmania (Leishmania) amazonensis</em>, with a particular focus on its impact on key biological and molecular parameters. Two distinct <em>Leishmania</em> lines (LaR-40 Line 1 and Line 2) were generated through stepwise <em>in vitro</em> selection with increasing concentrations of MTF, reaching up to 40 μM MTF. They were compared to their wild-type counterpart (LaWT). After 12 weeks of selection, LaR-40 promastigotes exhibited IC₅₀ values that were 4- to 8-fold higher than those of LaWT, with resistance remaining stable even after three months without drug pressure and following passage through BALB/c mice. No cross-resistance was detected against pentamidine, ketoconazole, or amphotericin B. MTF-resistant parasites exhibited reduced reactive oxygen species production, reduced lipid droplets (LD) abundance (in LaR-40 Line 1), delayed lesion onset, and smaller cutaneous lesions in mice, while maintaining normal infectivity in THP-1 macrophages. Quantitative RT-PCR analysis revealed consistent downregulation of the miltefosine transporter (<em>mt</em>) gene in both MTF-resistant lines, indicating that reduced drug uptake is the main mechanism underlying resistance. Line-specific changes, such as the upregulation of the serine palmitoyltransferase (<em>spt</em>) gene or the downregulation of the trypanothione reductase (<em>tryr</em>) gene, suggest that distinct metabolic pathways may act in a compensatory manner to reinforce resistance once transporter function is impaired. These findings indicate that MTF resistance in <em>L. amazonensis</em> is polygenic, stable, and adaptable. Routine monitoring of <em>mt</em> gene expression, combined with therapeutic strategies that target lipid or redox metabolism alongside drug uptake pathways, may help preserve the efficacy of current treatment regimens against leishmaniasis.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100617"},"PeriodicalIF":3.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185778","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":"Trialling the SmartWorm® application in New Zealand sheep farms","authors":"C.L. Brosnahan ,&nbsp;D. Warburton ,&nbsp;N. Cotter ,&nbsp;J.C. Tanner ,&nbsp;A.W. Greer","doi":"10.1016/j.ijpddr.2025.100616","DOIUrl":"10.1016/j.ijpddr.2025.100616","url":null,"abstract":"<div><div>Gastrointestinal nematodes (GIN) remain a major health and productivity challenge for grazing livestock globally, including New Zealand where widespread anthelmintic resistance has been reported. This was a pilot study evaluating the effectiveness of SmartWorm®, an app-based decision-support tool for Targeted Selective Treatment (TST) of internal parasites to reduce drench use without compromising lamb growth under New Zealand conditions.</div><div>A total of 1738 ewe lambs across three commercial farms were allocated to either a TST or Blanket Treatment (BT) group (treated every 28 days) and monitored over a 90-day period. All animals were drenched at the start of the trial, after which BT animals received treatment at each subsequent weighing. SmartWorm was used to determine drenching need for TST animals based on individual animal performance relative to expectation. Faecal egg counts (FEC), weight gain, and treatment frequency were assessed.</div><div>Across all farms, TST reduced anthelmintic use by 37–57 % compared with BT, with no significant differences in liveweight gain (P = 0.510). There was a weak but significant treatment effect on FEC (P = 0.01), and a linear relationship (R² = 0.8951, P &lt; 0.001 with one outlier removed) between BT group FEC and TST rate, indicating the system's responsiveness to parasite challenge.</div><div>This study demonstrates that implementing TST using this app can enable reduced anthelmintic use without compromising performance—an important step towards sustainable parasite management on New Zealand sheep farms.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100616"},"PeriodicalIF":3.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154724","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":"Transcriptional responses to in vitro macrocyclic lactone exposure in Toxocara canis larvae using RNA-seq","authors":"Theresa A. Quintana ,&nbsp;Matthew T. Brewer ,&nbsp;Jeba R.J. Jesudoss Chelladurai","doi":"10.1016/j.ijpddr.2025.100614","DOIUrl":"10.1016/j.ijpddr.2025.100614","url":null,"abstract":"<div><div><em>Toxocara canis</em>, the causative agent of zoonotic toxocariasis in humans, is a parasitic roundworm of canids with a complex life cycle. While macrocyclic lactones (MLs) are successful at treating adult <em>T. canis</em> infections when used at FDA-approved doses in dogs, they fail to kill somatic third-stage larvae. In this study, we profiled the transcriptome of third-stage larvae derived from larvated eggs and treated <em>in vitro</em> with 10 μM of the MLs ivermectin and moxidectin. We analyzed transcriptional changes in comparison with untreated control larvae. In ivermectin-treated larvae, we identified 608 differentially expressed genes (DEGs), of which 453 were upregulated and 155 were downregulated. In moxidectin-treated larvae, we identified 1413 DEGs, of which 902 were upregulated and 511 were downregulated. Notably, many DEGs were involved in critical biological processes and pathways including transcriptional regulation, energy metabolism, body structure and function, physiological processes such as reproduction, excretory/secretory molecule production, host-parasite response mechanisms, and parasite elimination. We also assessed the expression of known ML targets and transporters, including glutamate-gated chloride channels (GluCls), and ATP-binding cassette (ABC) transporters, subfamily B, with a particular focus on P-glycoproteins (P-gps). We present gene names for previously uncharacterized <em>T. canis</em> GluCl and transporter genes using phylogenetic analysis of nematode orthologs to provide uniform gene nomenclature. Our study revealed that the expression of two GluCls and eight ABCB genes, particularly five P-gps were significantly altered in response to ML treatment. Compared to controls, <em>Tca-glc-3</em>, <em>Tca-avr-14</em>, <em>Tca-haf-10</em>, and <em>Tca-Pgp-13.2</em> were downregulated in ivermectin-treated larvae, while <em>Tca-abcb7</em>, <em>Tca-Pgp-11.2</em>, and <em>Tca-Pgp-2</em> were downregulated in moxidectin-treated larvae. Conversely, <em>Tca-haf-9, Tca-Pgp-11.3,</em> and <em>Tca-Pgp-16.3</em> were upregulated in moxidectin-treated larvae. These findings suggest that MLs broadly impact transcriptional regulation in <em>T. canis</em> larvae.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100614"},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095077","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":"Ribosomal protein L27 contributes to virulence and maduramicin resistance in Eimeria tenella","authors":"Yu Yu ,&nbsp;Guo Huilin ,&nbsp;Liujia Li ,&nbsp;Guiquan Guan ,&nbsp;Qiping Zhao ,&nbsp;Shunhai Zhu ,&nbsp;Jinwen Wang ,&nbsp;Fanghe Zhao ,&nbsp;Hui Dong ,&nbsp;Hongyu Han","doi":"10.1016/j.ijpddr.2025.100615","DOIUrl":"10.1016/j.ijpddr.2025.100615","url":null,"abstract":"<div><div>Coccidiosis, which is primarily caused by <em>Eimeria</em> spp., poses a persistent challenge to poultry health and production worldwide. The emergence and spread of drug-resistant strains have significantly compromised the efficacy of anticoccidial therapies. We previously used RNA-seq to demonstrate that ribosomal protein L27 is differentially expressed in drug-sensitive and maduramicin-resistant strains of <em>E. tenella</em> (<em>Et</em>RPL27). In the present study, an RT–qPCR analysis showed that its expression is stage-specific, with the highest levels in sporozoites and second-generation merozoites. Immunofluorescence revealed both the cytoplasmic and partial surface localization of <em>Et</em>RPL27. Notably, <em>Et</em>RPL27 transcript levels were significantly elevated in a maduramicin-resistant strain relative to the drug-sensitive strain. Functional assays showed that anti-<em>Et</em>RPL27 antibodies inhibited the invasion of sporozoites, whereas the transgenic overexpression of <em>Et</em>RPL27 enhanced both the invasion efficiency and pathogenicity of <em>E. tenella</em> in chickens. Importantly, <em>Et</em>RPL27 overexpression reduced its sensitivity to maduramicin, evident as increased oocyst output and a higher anticoccidial index. Resistance classification based on standard indices confirmed moderate-to-high resistance levels in the <em>Et</em>RPL27-overexpressing strain. These findings demonstrate that <em>Et</em>RPL27 is closely associated with both virulence and maduramicin resistance in <em>E. tenella,</em> indicating its potential utility as a molecular marker and therapeutic target.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100615"},"PeriodicalIF":3.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154592","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":"Dual-targeting proteasome inhibitor ONX-0914 demonstrates potent antiplasmodial activity for malaria treatment","authors":"Nguyen Van Truong ,&nbsp;Tuyet-Kha Nguyen ,&nbsp;Nguyen Sy Thau ,&nbsp;Thi-Thanh Hang Chu ,&nbsp;Bazgha Sanaullah ,&nbsp;Ch Venkataramaiah ,&nbsp;Jin-Hee Han ,&nbsp;Sung-Hun Na ,&nbsp;Won-Sun Park ,&nbsp;Wan-Joo Chun ,&nbsp;Joo Hwan No ,&nbsp;Eun-Taek Han","doi":"10.1016/j.ijpddr.2025.100613","DOIUrl":"10.1016/j.ijpddr.2025.100613","url":null,"abstract":"<div><div>There is an urgent need to discover novel antimalarial drugs that are safe and provide effective cures with broad therapeutic potential, novel mechanisms of action, and suitable pharmacokinetic profiles. We studied ONX-0914, which targets the proteolytic system of eukaryotic cells and has been effective against cancer and immune disorders. The antiplasmodial activity and safety of ONX-0914 were investigated both <em>in vitro</em> and <em>in vivo</em>, along with its mechanism of action and potential bioavailability. Notably, ONX-0914 strongly inhibited the proliferation of various <em>Plasmodium falciparum</em> strains, including chloroquine (CQ)- and artesunate (ART)-sensitive and -resistant strains, with a low nanomolar IC₅₀ (&lt;50nM). It also exhibited potent synergistic activity with ART, blocking the proliferation of ART- and CQ-resistant strains, while showing low toxicity to human cells (CC₅₀ &gt; 100 μM). The potent antiplasmodial activity of ONX-0914 is attributed to the dual inhibition of haemoglobin metabolism and the ubiquitin‒proteasome system. <em>In vivo</em> results revealed that ONX-0914 suppressed <em>P. berghei</em> ANKA parasites by &gt; 95 % after 4 days of treatment and increased survival rate and mean survival time following a single dose administered via various routes (effect dose ED₅₀ of 7.62 mg/kg per oral [PO] and 6.52 mg/kg intraperitoneal [IP], and intravenous [IV]). ONX-0914 treatment resulted in a low recrudescence rate after one month (&lt;2 %), reduced organ lesions (brain, heart, lung, liver, spleen, and kidney) compared to untreated controls, and favourable pharmacokinetic parameters (AUC &gt;20,960 h∗μg/ml, T_1/2 = 7.9 h [IV], 0.7 h [PO], C _max = 10708.2 μg/ml [PO], bioavailability = 23.83 %), supporting its antimalarial efficacy. Owing to its low toxicity, robust antiplasmodial activity through a combination mechanism, and supportive pharmacokinetic properties, ONX-0914 is a promising antimalarial agent.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100613"},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118501","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":"Faecal egg count reduction test, deep amplicon sequencing of isotype-1 β-tubulin gene and in ovo larval development assay reveal susceptibility to benzimidazoles of porcine nematodes Oesophagostomum spp. and Ascaris suum in outdoor-reared pigs in Germany","authors":"Hannah RM. Fischer ,&nbsp;Jürgen Krücken ,&nbsp;Stefan Fiedler ,&nbsp;Stig M. Thamsborg ,&nbsp;Hendrik Nienhoff ,&nbsp;Stephan Steuber ,&nbsp;Ricarda Daher ,&nbsp;Georg von Samson-Himmelstjerna","doi":"10.1016/j.ijpddr.2025.100612","DOIUrl":"10.1016/j.ijpddr.2025.100612","url":null,"abstract":"<div><div><em>Oesophagostomum</em> spp. and <em>Ascaris suum</em> represent the most common porcine nematodes and anthelmintic resistance (AR) to various anthelmintics has been reported for <em>Oesophagostomum</em>. However, the current AR status for worm populations on German farms and practical methods facilitating reliable AR detection are missing. Herein, the efficacy of benzimidazoles (BZ) (fenbendazole, 5 mg/kg body weight, single dose) was analysed on 13 farms with outdoor access. The Faecal Egg Count Reduction Test (FECRT) estimates for strongyles on the farms (range 99.8–100 %) exceeded the target efficacy (99 %) of the new W.A.A.V.P. guideline for <em>Oesophagostomum dentatum.</em> Deep amplicon sequencing was used for the first time for porcine nematodes and revealed no polymorphisms associated with BZ-resistance in codons 134, 167, 198 and 200 of the isotype-1 β-tubulin gene. Nemabiome analysis using ITS-2 deep amplicon sequencing, based on two pre- and post-treatment samples, showed a significant increase (p &lt; 0.001) of <em>Oesophagostomum quadrispinulatum</em> after BZ treatment. For <em>A. suum,</em> the interpretation of FECRT estimates can be hindered due to coprophagy-associated false-positive egg counts in pigs. Therefore, two FECRT analysis for <em>A. suum</em> were pursued, the first analyses included all EPG data, the second considered EPGs &lt;200 pre- and post-treatment as negative. An <em>in ovo</em> larval development assay (LDA) was developed for the <em>in vitro</em> analysis of BZ-susceptibility in <em>A. suum</em>. Computed EC₅₀ values ranged from 1.50 to 3.36 μM thiabendazole (mean 2.24 μM). An EC₅₀ of 3.90 μM thiabendazole (mean EC₅₀ + 3 × SD) as provisional cut-off for detection of resistant populations is suggested. In conclusion, no AR was detected in <em>Oesophagostomum</em> using the FECRT and β-tubulin deep amplicon sequencing. For <em>A. suum</em> the FECRT results were ambiguous<em>,</em> in some cases even when excluding the low egg counts from calculations. With the <em>in ovo</em> LDA all investigated <em>A. suum</em> populations were identified as susceptible to BZ.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100612"},"PeriodicalIF":3.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932528","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}