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

{"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":"2025-12-01","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":"A novel intron variant is associated with emerging pfdhps mutant haplotypes in West and Central African Plasmodium falciparum","authors":"Emma Filtenborg Hocke ,&nbsp;Helle Hansson ,&nbsp;Ana Chopo-Pizarro ,&nbsp;Adebanjo Jonathan Adegbola ,&nbsp;Oluseye Bolaji ,&nbsp;Peter Thelma Ngwa Niba ,&nbsp;Innocent Mbulli Ali ,&nbsp;Akindeh Nji ,&nbsp;Wilfred Mbacham ,&nbsp;Vito Baraka ,&nbsp;Neema B. Kulaya ,&nbsp;Gauthier Mesia Kahunu ,&nbsp;Hypolite Muhindo Mavoko ,&nbsp;Papy Mandoko Nkoli ,&nbsp;Eric Mukomena Sompwe ,&nbsp;Destin Mbongi ,&nbsp;Patrick Mitashi ,&nbsp;Valérie A. Bédia ,&nbsp;Paterne A. Gnagne ,&nbsp;Abibatou Konaté ,&nbsp;Cally Roper","doi":"10.1016/j.ijpddr.2025.100611","DOIUrl":"10.1016/j.ijpddr.2025.100611","url":null,"abstract":"<div><div>Sulfadoxine-pyrimethamine plays a key role in <em>Plasmodium falciparum</em> chemoprevention across Africa, yet the protective efficacy of SP is undermined by mutations conferring resistance in the genes encoding dihydrofolate reductase (<em>pfdhfr</em>) and dihydropteroate synthase (<em>pfdhps</em>). The emergence and spread of the <em>pfdhps</em> 431V mutation suggests that this may confer resistance and be selected by drug use. Here, we report a non-coding mutation a548383t, which expands a di-nucleotide repeat in the first intron of <em>pfpppk-dhps</em>. The first intron and second exon of the <em>pfdhps</em> gene were analysed by target amplicon sequencing of 929 <em>P. falciparum</em>-positive blood samples from Nigeria, Cameroon, Tanzania, The Democratic Republic of Congo, and Côte d’Ivoire. The intron mutation was found in Nigeria, Côte d’Ivoire, and Cameroon in association with the 431V mutation. In particular, the intron mutation was most highly associated with the <strong>VAG</strong>K<strong>GS</strong> haplotype (OR = 211.7, P &lt; 0.001), followed by the <strong>VAG</strong>KA<strong>S</strong> (OR = 39.2, P &lt; 0.001), and <strong>VAG</strong>KAA (OR = 33.6, P &lt; 0.001) haplotypes. Additionally, a reduced di-nucleotide repeat diversity was observed in 431V-positive variants. The intron variant is significantly associated with the 431V mutation which is consistent with previous reports of selective sweeps around <strong>VAG</strong>K<strong>GS.</strong> The association of the 548383t mutation with both <strong>VAG</strong>K<strong>GS, VAG</strong>KA<strong>S</strong> and <strong>VAG</strong>KAA might indicate these lineages either have a common ancestor or that the intron variant 548383t has a functional association with 431V. More research is needed to determine if the association is simply genetic hitchhiking, or if the intron variant confers a phenotypic advantage.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100611"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908311","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":"2025-12-01","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":"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":"2025-12-01","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":"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":3.5,"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":"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":"2025-12-01","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":"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":"2025-12-01","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":"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":"Combination astragaloside IV and artesunate preserves blood–brain barrier integrity by modulating astrocytes and tight junction proteins in Plasmodium yoelii infection","authors":"Phornyupa Sanguanwong ,&nbsp;Ladawan Khowawisetsut ,&nbsp;Lanaprai Kwathai ,&nbsp;Peeraporn Varinthra ,&nbsp;Chairat Turbpaiboon ,&nbsp;Panapat Uawithya ,&nbsp;Prasert Sobhon ,&nbsp;Ingrid Y. Liu ,&nbsp;Supin Chompoopong","doi":"10.1016/j.ijpddr.2025.100598","DOIUrl":"10.1016/j.ijpddr.2025.100598","url":null,"abstract":"<div><h3>Background</h3><div>Astragaloside IV (ASIV), a natural compound from <em>Astragalus membranaceus</em>, exerts neuroprotective and anti-inflammatory effects in various pathologies. Its role in <em>Plasmodium yoelii</em> (Py) 17XL–induced inflammation leading to blood–brain barrier (BBB) damage remains undefined. Artesunate (ART), the frontline therapy for severe malaria, has encountered resistance and unresolved neurological sequelae. This study investigated the anti-inflammatory properties of ASIV combined with ART in Py-infected mice.</div></div><div><h3>Methods</h3><div>Sixty-five Institute of Cancer Research mice were randomized into 5 groups: sham, Py, Py-ART, Py-ASIV, and Py-ASIV + ART. Mice in Py groups were infected with Py 17XL. Either 25 mg/kg ASIV alone or 25 mg/kg ASIV plus 2.4 mg/kg ART was administered intraperitoneally for 5 days. Survival rate/time, parasitemia, neurological status, histopathology, and biochemical indices were evaluated.</div></div><div><h3>Results</h3><div>Although ASIV alone partially suppressed parasitemia, combination therapy significantly prolonged survival and mitigated neurological deficits. Both ASIV and ASIV + ART reduced IL-1β and TNF-α expression in serum and brain, attenuated BBB leakage (Evans blue assay), and preserved BBB integrity by decreasing astrocytic glial fibrillary acidic protein and aquaporin-4 while upregulating the tight junction proteins occludin and zonula occludens-1.</div></div><div><h3>Conclusions</h3><div>ASIV exhibited modest antiparasitic action and robust anti-inflammatory effects, alleviating BBB disruption when combined with ART in Py 17XL–infected mice. These findings provide an essential basis for further preclinical exploration of ASIV as an adjunct therapy in severe malaria.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100598"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196339","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}