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

{"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}

{"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":"2025-08-26","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":"In vitro antiplasmodial activities of extract and fractions from Lepidobotrys staudtii against sensitive and resistant blood-stage parasites of Plasmodium falciparum","authors":"Jeannette Nina Magoudjou Pekam ,&nbsp;Noella Molisa Efange ,&nbsp;Lakshminarayana Mishro ,&nbsp;Rodrigue Keumoe ,&nbsp;Bruno Lenta Ndjakou ,&nbsp;Lawrence Ayong ,&nbsp;Frédéric Nico Njayou ,&nbsp;Paul Fewou Moundipa ,&nbsp;Vinoth Rajendran","doi":"10.1016/j.ijpddr.2025.100610","DOIUrl":"10.1016/j.ijpddr.2025.100610","url":null,"abstract":"<div><div>Antimalarial resistance is a primary challenge in the treatment of malaria. The ongoing search for novel drug sources remains a critical strategy for addressing this issue. This study evaluated the blood stage antiplasmodial and cytotoxic activities of the crude extract and fractions obtained from <em>Lepidobotrys staudtii</em>. The crude extract and all fractions exhibited promising antiplasmodial activity (IC₅₀ &lt; 10 μg/mL) against all the tested <em>Plasmodium falciparum</em> strains (<em>Pf</em>3D7 drug-sensitive and <em>Pf</em>INDO chloroquine-resistant). Notably, the hexane and ethyl acetate fractions exhibited the highest potency, with IC₅₀ values of 3.73 and 3.4 μg/mL (<em>Pf</em>3D7), respectively. No cytotoxic effects were observed at concentrations of up to 500 μg/mL. The ethyl acetate fraction displayed rapid action (12 h of exposure) against the <em>Pf</em>3D7 and <em>Pf</em>INDO strains. The ring stage parasites were particularly susceptible to the fractions, with IC₅₀ values ranging from 2.17 to 4.87 μg/mL (<em>Pf</em>3D7) and 2.27–6.27 μg/mL (<em>Pf</em>INDO). Additionally, combining the fraction with standard antimalarials at fixed sub-inhibitory concentrations significantly reduced IC₅₀ values. Only the hexane and crude extracts stimulated reactive oxygen species (ROS) production, whereas the other fractions neutralized the ROS. The most potent ethyl acetate fraction arrested parasite developmental progression and merozoite egress. Phytochemical analyses revealed the presence of phenols, flavonoids, tannins, alkaloids, saponins, carbohydrates, glycosides, and proteins. Reverse Phase High Performance Liquid Chromatography (RP-HPLC) analysis revealed that the fractions comprised a diverse array of compounds, resulting in varying levels of parasite-killing. This study emphasizes the blood-stage antiplasmodial properties of the stem bark extract and fractions of <em>L. staudtii</em>, underscoring their potential as a promising source of antimalarial agents.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100610"},"PeriodicalIF":3.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010128","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":"In vitro screening of the open-access Pandemic Response Box reveals ESI-09 as a compound with activity against Echinococcus multilocularis","authors":"Pascal Zumstein ,&nbsp;Anissa Bartetzko ,&nbsp;Marc Kaethner ,&nbsp;Laura Vetter ,&nbsp;Andrew Hemphill ,&nbsp;Trix Zumkehr ,&nbsp;Benoît Laleu ,&nbsp;Matías Preza ,&nbsp;Britta Lundström-Stadelmann","doi":"10.1016/j.ijpddr.2025.100609","DOIUrl":"10.1016/j.ijpddr.2025.100609","url":null,"abstract":"<div><div>Alveolar echinococcosis (AE) is a life-threatening disease caused by the metacestode stage of the fox tapeworm <em>Echinococcus multilocularis</em>, primarily in the liver. Current drug treatments rely on benzimidazoles, which are not parasiticidal, requiring life-long therapy with significant side effects. Therefore, novel drug treatments are urgently needed. Drug repurposing offers a strategy to identify novel therapies against the neglected disease AE. We report on the <em>in vitro</em> screening of the Pandemic Response Box, an open-access compound library composed of 400 drug-like molecules assembled by Medicines for Malaria Venture (MMV) and the Drugs for Neglected Disease Initiative (DNDi), against <em>E. multilocularis</em>. An overview screen at 10 μM using the metacestode vesicle damage-marker release assay (based on release of phosphoglucose isomerase, PGI) and metacestode vesicle viability assay (based on ATP measurement) identified 37 active compounds. Reassessment in triplicates resulted in five active compounds (alexidine, carbendazim, ESI-09, MMV1581545, oxfendazole) displaying anti-metacestode activity. The parasiticidal activity of these five compounds was evaluated by ATP measurement in germinal layer cells. One compound, ESI-09, acted specifically against <em>E. multilocularis</em> (IC₅₀ on metacestode vesicles 6.06 ± 3.18 μM by PGI release assay and 2.09 ± 0.56 μM by metacestode vesicle viability assay as well as an IC₅₀ of 2.45 ± 0.86 μM on germinal layer cells) with a broad therapeutic window when compared to mammalian cell toxicity. Further experiments applying Seahorse technology and tetramethylrhodamine ethyl ester (TMRE) assay revealed that ESI-09 acts as a mitochondrial uncoupler in parasite cells. However, transmission electron microscopy showed no significant ultrastructural changes in parasite mitochondria, though increased secretion of extracellular vesicle-like structures between the tegument and the laminated layer was observed. In summary, screening of the Pandemic Response Box identified ESI-09 as a potential drug candidate for the treatment of AE. Further experiments are needed to evaluate the efficacy of ESI-09 <em>in vivo</em>.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100609"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908231","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":"Antiplasmodial activity of pentyloxyamide-based histone deacetylase inhibitors against Plasmodium falciparum parasites","authors":"Wisam A. Dawood ,&nbsp;Gillian M. Fisher ,&nbsp;Josefa Kremeyer ,&nbsp;Fabian Fischer ,&nbsp;Jessica L. Home ,&nbsp;Christopher D. Goodman ,&nbsp;Kwong Sum Lam ,&nbsp;Alexander G. Maier ,&nbsp;Thomas Kurz ,&nbsp;Katherine T. Andrews","doi":"10.1016/j.ijpddr.2025.100608","DOIUrl":"10.1016/j.ijpddr.2025.100608","url":null,"abstract":"<div><div>Malaria is caused by <em>Plasmodium</em> parasites and remains a significant health concern for almost half the world's population. There are estimated to be &gt; 240 million malaria cases and approximately 600,000 malaria-related deaths annually, mainly due to infection with <em>P. falciparum</em> parasites. Parasite drug resistance is impacting malaria prevention and control efforts, and as part of the malaria eradication agenda, new drugs with novel mechanisms of action are needed. Histone/lysine deacetylase (HDAC) enzymes play essential roles in <em>Plasmodium</em> biology and are potential targets for the development of new antiplasmodial agents. In this study, a panel of 24 HDAC inhibitors with hydroxamic acid zinc binding group, a pentyloxyamide connecting unit linker region and substituted 4-phenyl and 4(pyridinyl)thiazole cap groups were investigated for <em>in vitro</em> activity against asexual intraerythrocytic stage <em>P. falciparum</em> parasites, the life cycle stage responsible for the clinical symptoms of malaria. The most potent compound (<strong>4o</strong>) had a <em>P. falciparum</em> IC₅₀ of 20 nM and &gt;250-fold greater selectivity for <em>P. falciparum</em> versus human cells. Compound <strong>4o</strong> was also active against exoerythrocytic stage parasites (IC₅₀ 24 nM), which are a target for malaria prevention. In contrast, <strong>4o</strong> lacked potent activity against late-stage gametocytes (IC₅₀ &gt; 2 μM), which are a target for malaria transmission-blocking drugs. Compound <strong>4o</strong> and analogues caused <em>in situ</em> hyperacetylation of <em>P. falciparum</em> histone H4, indicating deacetylase inhibition. Furthermore, <strong>4o</strong> was found to stabilise <em>Pf</em>HDAC1 in <em>P. falciparum</em> protein lysates using solvent-induced protein stability Western blot assays with anti-<em>Pf</em>HDAC1 antibody. Together, these data provide new structure-activity relationship and mechanistic insights on pentyloxyamide-based HDAC inhibitors as potential therapeutic starting points for malaria.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100608"},"PeriodicalIF":3.4,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890187","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}