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

{"title":"Unpacking boxes: identification of novel inhibitors of malaria parasite invasion.","authors":"Claudia Bg Barnes, Molly Parkyn Schneider, Olivia D Ventura, Zahra Razook, Kirsty McCann, Coralie Boulet, Alysha H Literski, Alyssa E Barry, Brad E Sleebs, Brendan S Crabb, Paul R Gilson, Hayley E Bullen","doi":"10.1016/j.ijpddr.2026.100647","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2026.100647","url":null,"abstract":"<p><p>With resistance to current frontline antimalarial treatments rapidly emerging in malaria endemic regions, there is an urgent need to identify new antimalarial compounds with novel mechanisms of action. Currently, no clinically used antimalarials target erythrocyte invasion, the process by which the short-lived, extracellular merozoite form of Plasmodium falciparum parasites enters a host erythrocyte. Following invasion, the parasite grows and then divides to form a schizont, containing merozoites that exit the host cell and invade new erythrocytes. To identify novel egress and invasion inhibitors, we screened the Medicines for Malaria Venture COVID Box (160 compounds) and Global Health Priority Box (240 compounds). Parasites were treated with the compounds at 1 μM during the egress and invasion period and across both libraries, 20 invasion inhibitors and two partial egress inhibitors were identified. A comparison of the growth IC₅₀ and invasion IC₅₀ of each hit compound revealed that invasion inhibition is likely central to the parasiticidal mechanism of six of the compounds, as their IC₅₀s for growth and invasion were similar. Of these six inhibitors, two (MMV006931 and MMV024850) were found to directly block the invasion of mechanically purified merozoites. We sought to identify the protein targets of these compounds through resistance selection and subsequent whole genome sequencing. We were able to select parasites with robust resistance to MMV006931 but not MMV024850. Genome sequencing of clonal MMV006931-resistant parasites identified mutations in the P. falciparum sterol exporter PfNCR1, which helps eliminate excess cholesterol from the parasite's plasma membrane. By demonstrating that MMV006931 sensitises parasites to lysis by a sterol-dependent detergent, we confirmed that PfNCR1 is the likely target of MMV006931.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"31 ","pages":"100647"},"PeriodicalIF":3.4,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837399","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":"Efficacy of phosphonium amphiphilic salts against Acanthamoeba genotype T4","authors":"Miloš Lukáč ,&nbsp;Martin Pisárčik ,&nbsp;Mária Garajová ,&nbsp;Julia Walochnik ,&nbsp;Daniela Ošustová ,&nbsp;Eva Vatrtová ,&nbsp;Iryna Bondar ,&nbsp;Ferdinand Devínsky ,&nbsp;Martin Mrva","doi":"10.1016/j.ijpddr.2026.100636","DOIUrl":"10.1016/j.ijpddr.2026.100636","url":null,"abstract":"<div><div>Acanthamoebae are opportunistic pathogens causing serious human infections, including granulomatous amoebic encephalitis (GAE) and <em>Acanthamoeba</em> keratitis (AK). The treatment of those infections is limited and difficult to date. Recent research demonstrated high antimicrobial activity of phosphonium amphiphilic salts. In the present work we aimed to investigate the anti-<em>Acanthamoeba</em> effect of a series of 16 phosphonium salts. The structure of these synthesized cationic amphiphiles was modified in both the polar and nonpolar parts of the surfactant molecule. The compounds have different alkyl chain lengths (C12 - C18) and different numbers of methyl and phenyl groups (0 - 3) attached to the quaternary phosphorus atom. The following basic physicochemical properties of the compounds were determined: critical micelle concentration (cmc), the surface tension value at the cmc and the surface area per surfactant head group. The cmc values, which express the degree of lipophilicity of compounds, were correlated with biological activities. The effects of phosphonium salts on trophozoites of <em>Acanthamoeba quina</em> and <em>Acanthamoeba hatchetti</em> (both strains of genotype T4) and human erythrocytes were studied. The highest trophocidal activity was recorded for the compound <strong>C₁₆P(Me)₂PhBr</strong> with the minimal trophocidal concentration (MTC) of 7.8 μM for the <em>A. quina</em> strain and 15.6 μM for the <em>A. hatchetti</em> strain, after 24 h. Its activity was comparable or higher than the activity of drugs currently used in the treatment of <em>Acanthamoeba</em> keratitis. Therefore, this compound is a promising candidate in the fight against infections caused by <em>Acanthamoeba</em>.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100636"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142452","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":"Ferrostatin-1 alleviates experimental cerebral malaria by regulating immune cell functions and brain endothelial ferroptosis","authors":"Shijie Yao ,&nbsp;Xiaoliang Zhou ,&nbsp;Ting Liao ,&nbsp;Chao Yao ,&nbsp;Mengna Sun ,&nbsp;Haojie Gou ,&nbsp;Xueyuan Hu ,&nbsp;Junyu Liu ,&nbsp;Li Zheng ,&nbsp;Yan Zhao ,&nbsp;Yaming Cao","doi":"10.1016/j.ijpddr.2025.100630","DOIUrl":"10.1016/j.ijpddr.2025.100630","url":null,"abstract":"<div><div>Cerebral malaria (CM), a life-threatening complication of <em>Plasmodium falciparum</em> infection, is characterized by dysregulated immune responses and blood-brain barrier (BBB) damage. In this study, we found that iron metabolic disorders occurred in the spleen and brain tissues in response to <em>Plasmodium berghei</em> ANKA (PbA) infection in a murine CM model. PbA infection promoted lipid peroxidation and induced ferroptosis, manifested as the accumulation of iron ion, elevation of reactive oxygen species and lipid peroxide, upregulated expression of the ferroptosis-related protein TFRC and ACSL4, and downregulated expression of SLC7A11 and GPX4. Ferrostatin-1 (Fer-1), is widely used as a reference compound as a synthetic radical-trapping antioxidant, which inhibits ferroptosis by suppressing lipid peroxide formation. Intervention with Fer-1 ameliorated iron metabolic disorders, reduced lipid peroxidation, decreased parasitemia, extended survival time, alleviated neurological symptoms, and improved BBB integrity. Mechanistically, Fer-1 exerted dual-axis regulation: firstly, enhancing the antigen-presenting capacity of dendritic cells (DCs) by upregulating MHC II, CD80/86, promoting M1 polarization of macrophages, modulating CD4⁺ T cell responses to increase IFN-γ⁺ Th1 cells and Treg cell proportions for balancing pro-inflammatory and anti-inflammatory reactions; secondly inhibiting ferroptosis in brain microvascular endothelial cells, downregulating chemokines CXCL9/CXCL10 and adhesion molecules ICAM-1/VCAM-1, and reducing cerebral infiltration of CD8⁺ T cells. Our study confirms that Fer-1 alleviates ECM pathological progression through dual mechanisms \"immune activation-endothelial protection\", providing a novel ferroptosis-targeted strategy for CM prevention and treatment.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100630"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789971","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":"Pharmacokinetics of fenbendazole and its bioactive metabolite oxfendazole in northern bobwhite administered an anthelmintic feed","authors":"Hannah N. Suber ,&nbsp;Dhavalkumar Patel ,&nbsp;Timothy B. Arlowe ,&nbsp;Ashley Kaskocsak ,&nbsp;Henry Valencia ,&nbsp;Kaya Kinsey ,&nbsp;Will R. Robinson ,&nbsp;Ronald J. Kendall","doi":"10.1016/j.ijpddr.2026.100640","DOIUrl":"10.1016/j.ijpddr.2026.100640","url":null,"abstract":"<div><div>The northern bobwhite (<em>Colinus virginianus</em>) has experienced significant population declines across its native range. Parasitic nematodes are increasingly being recognized as contributing factors. QuailGuard®, an anthelmintic feed that uses fenbendazole (FBZ) as the active ingredient, has shown promise in field studies for reducing parasite loads in wild quail. However, little is known about the pharmacokinetics of FBZ in bobwhite, limiting accurate assessments of therapeutic exposure. This study investigated the pharmacokinetic profile of FBZ and its bioactive metabolite, oxfendazole (OFZ), in bobwhite fed QuailGuard®. Plasma concentrations were measured at multiple time points during (1, 2, 4, 8, and 24 h) and after (2, 4, 8, 24, and 32 h) feed administration using LC/MS-MS. Key pharmacokinetic parameters, including estimated area under the curve (AUC), apparent elimination rate, half-life, and mean residence time (MRT) were calculated using composite sampling. Peak average plasma concentrations of FBZ (2.3701 μg/mL) and OFZ (0.5526 μg/mL) occurred at 8 h post-ingestion. Estimated AUCs were 47.782 μg h/mL for FBZ and 12.783 μg h/mL for OFZ, with respective half-lives of 3.83 and 4.03 h. Combined drug exposure approached levels associated with the lethality of <em>Oxyspirura petrowi</em> in prior studies, indicating that intake over multiple weeks may achieve therapeutic efficacy. While sex did not affect analyte accumulation during treatment, females exhibited faster OFZ apparent elimination than males. FBZ and OFZ were rapidly absorbed and eliminated, which supports the safety of QuailGuard® for use in wild populations. These findings establish foundational pharmacokinetic data necessary for optimizing field treatment regimens and improving parasite control strategies in declining bobwhite populations.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100640"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616142","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":"Prevalence of antimalarial drug resistance molecular markers in Makenene, central Cameroon","authors":"Nelly Armanda Kala-Chouakeu ,&nbsp;Joel Djoufounna ,&nbsp;Nicolas Benoit ,&nbsp;Timoléon Tchuinkam ,&nbsp;Océane Delandre ,&nbsp;Lionel Almeras ,&nbsp;Roland Bamou ,&nbsp;Christophe Antonio-Nkondjio ,&nbsp;Marylin Madamet ,&nbsp;Bruno Pradines","doi":"10.1016/j.ijpddr.2026.100633","DOIUrl":"10.1016/j.ijpddr.2026.100633","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Antimalarial drug resistance remains a significant challenge in the fight against malaria in Cameroon. Given the high prevalence of malaria in Makenene in central Cameroon and the limited knowledge of drug resistance profiles in the area, the prevalence of &lt;em&gt;Plasmodium falciparum&lt;/em&gt; drug resistance genetic markers was assessed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;185 samples from asymptomatic individuals with &lt;em&gt;P. falciparum&lt;/em&gt; parasitaemia collected between September and October 2021 were sequenced for the &lt;em&gt;Pfdhfr&lt;/em&gt;, &lt;em&gt;Pfdhps&lt;/em&gt;, &lt;em&gt;Pfcrt&lt;/em&gt;, &lt;em&gt;Pfmdr1,&lt;/em&gt; and &lt;em&gt;PfK13&lt;/em&gt; genes.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;One hundred percent of the samples harboured parasites with triple mutant &lt;em&gt;Pfdhfr&lt;/em&gt; &lt;strong&gt;I&lt;/strong&gt;&lt;sub&gt;51&lt;/sub&gt;&lt;strong&gt;R&lt;/strong&gt;&lt;sub&gt;59&lt;/sub&gt;&lt;strong&gt;N&lt;/strong&gt;&lt;sub&gt;108&lt;/sub&gt;I&lt;sub&gt;164&lt;/sub&gt; (&lt;strong&gt;IRN&lt;/strong&gt;I), associated with high level of resistance to pyrimethamine. The septuple mutant &lt;em&gt;Pfdhfr&lt;/em&gt; &lt;strong&gt;IRN&lt;/strong&gt;I and &lt;em&gt;Pfdhps&lt;/em&gt; &lt;strong&gt;A&lt;/strong&gt;&lt;sub&gt;436&lt;/sub&gt;&lt;strong&gt;G&lt;/strong&gt;&lt;sub&gt;437&lt;/sub&gt;K&lt;sub&gt;540&lt;/sub&gt;&lt;strong&gt;G&lt;/strong&gt;&lt;sub&gt;581&lt;/sub&gt;&lt;strong&gt;S&lt;/strong&gt;&lt;sub&gt;613&lt;/sub&gt; (&lt;strong&gt;AG&lt;/strong&gt;K&lt;strong&gt;GS&lt;/strong&gt;), associated with resistance to sulfadoxine-pyrimethamine, was detected in 62.0 % of the isolates. The new &lt;em&gt;Pfdhps&lt;/em&gt; I431V mutation was observed in 18.8 %. The octuple mutant &lt;strong&gt;IRN&lt;/strong&gt;I + &lt;strong&gt;VAG&lt;/strong&gt;K&lt;strong&gt;GS&lt;/strong&gt; haplotype, overrepresented in pregnant women taking intermittent preventive treatment with sulfadoxine-pyrimethamine, was found in 17.4 %. The &lt;em&gt;Pfdhps&lt;/em&gt; K540E mutation, linked to “super” resistance to sulfadoxine, was only detected in 1.9 %. The &lt;em&gt;Pfcrt&lt;/em&gt; C&lt;sub&gt;72&lt;/sub&gt;V&lt;sub&gt;73&lt;/sub&gt;&lt;strong&gt;I&lt;/strong&gt;&lt;sub&gt;74&lt;/sub&gt;&lt;strong&gt;E&lt;/strong&gt;&lt;sub&gt;75&lt;/sub&gt;&lt;strong&gt;T&lt;/strong&gt;&lt;sub&gt;76&lt;/sub&gt; haplotype, implicated in chloroquine resistance, was absent in Makenene. The &lt;em&gt;Pfmdr1&lt;/em&gt; N&lt;sub&gt;86&lt;/sub&gt;&lt;strong&gt;F&lt;/strong&gt;&lt;sub&gt;184&lt;/sub&gt; haplotype, selected in parasites with a recrudescence in patients treated with artemether-lumefantrine, was found in 73.2 %. No isolate harboured the &lt;strong&gt;Y&lt;/strong&gt;&lt;sub&gt;86&lt;/sub&gt;Y&lt;sub&gt;184&lt;/sub&gt; haplotype, selected in parasites with recrudescence in patient treated with dihydroartemisinin-piperaquine. Moreover, no mutation associated with artemisinin partial resistance was detected in &lt;em&gt;PfK13&lt;/em&gt;.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The in-depth analysis of genetic mutations associated with antimalarials resistance in this study, notably those with a high prevalence of mutations on the &lt;em&gt;Pfdhfr&lt;/em&gt; and &lt;em&gt;Pfdhps&lt;/em&gt; genes, highlights the immediate need for proactive strategies to combat resistance in Makenene. Continuous monitoring, including molecular and in vivo surveillance is crucial to uphold the effectiveness of current treatments and, more particularly, artemisinin-based combination therapies, and to enable better decision-making on effective treatment policy i","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100633"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022784","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":"Anti-cryptosporidial efficacy of tricyclic carbazole aminoalcohols in vitro and in vivo","authors":"Mingxiao Liu ,&nbsp;Weisi Wang ,&nbsp;Qi Zheng ,&nbsp;Di Zhang ,&nbsp;Dongqiang Wang ,&nbsp;Chenchen Wang ,&nbsp;Jigang Yin ,&nbsp;Liping Duan ,&nbsp;Guan Zhu","doi":"10.1016/j.ijpddr.2026.100631","DOIUrl":"10.1016/j.ijpddr.2026.100631","url":null,"abstract":"<div><div>Cryptosporidiosis is a major cause of diarrheal disease in humans and animals, yet there are no fully effective drugs, particularly for immunocompromised patients. Carbazole aminoalcohols (CAAs) are a relatively unexplored chemical class with reported broad-spectrum antiparasitic activities. Here, we systematically evaluated 36 CAA derivatives for anti-cryptosporidial efficacy. In vitro screening using a 44-h <em>Cryptosporidium parvum</em> infection assay identified eight compounds with low-micromolar EC₅₀ values (1.53–6.86 μM). The three most potent hits (H1402 at 25 mg/kg/d, and YFM1 and YFM3 at 15 mg/kg/d) were selected for in vivo evaluation in a chronic <em>C. tyzzeri</em> mouse model. Daily oral treatment with these compounds for 7 days reduced fecal oocyst shedding by 55.9–59.1 % compared with a 247.5 % increase in vehicle controls (<em>P</em> &lt; 0.01). Paromomycin at 1000 mg/kg/d, used as a positive control, produced an 84.2 % reduction. All three CAAs were generally well tolerated, with only minor weight loss observed in H1402-treated mice. Together, these results demonstrate that CAAs possess reproducible in vitro activity and significant in vivo efficacy against cryptosporidial infection, supporting their potential as lead scaffolds for anti-cryptosporidial drug development. Structural optimization to improve potency, selectivity, and pharmacokinetic properties is warranted to advance CAAs toward preclinical development.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100631"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of quadruplex droplet digital PCR assay for rapid detection of molecular markers associated with macrocyclic lactone resistance and susceptibility in Dirofilaria immitis","authors":"Sohini Kumar,&nbsp;Isabelah Kassandra Lalicon,&nbsp;Roger K. Prichard,&nbsp;Thavy Long","doi":"10.1016/j.ijpddr.2025.100625","DOIUrl":"10.1016/j.ijpddr.2025.100625","url":null,"abstract":"<div><div>Due to climate change and human interventions, there has been an increase in <em>D. immitis</em> infections, underscoring the necessity for monitoring the spread and extent of resistance. In our prior research, we introduced a rapid test utilizing four predominant SNP markers at loci 15709 (SNP1), 30575 (SNP2), 21554 (SNP3), and 9400 (SNP7) linked to ML resistance. Our findings highlighted SNP1 and SNP2 as potent predictive markers, offering suitability for the rapid detection and monitoring of drug resistance. Therefore, we developed a cost-effective test using droplet digital PCR (ddPCR) technology to perform a quadruplex assay to assess alternate allele frequency. Our assay can identify both SNP1 and SNP2 wildtype and mutant targets in a single sample. We tested the performance of our 4-plex assay on 8 laboratory-maintained isolates, including Missouri (MO), Berkeley, JYD-34, Metairie-2014, Yazoo-2013, GA-2, GA-3, and Big Head, and further validated the sensitivity using clinical isolates from the United States. Our assay demonstrated consistent results compared to the standard MiSeq sequencing and ddPCR duplex assay. Notably, we showcased the utility of ddPCR for direct genotyping of <em>D. immitis</em> infected whole blood from two well-characterized isolates, MO and JYD-34. This approach streamlined the assay workflow and lowered costs, thus enhancing affordability for larger genotyping studies.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100625"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010173","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":"The EamA metabolite transporter does not affect antileishmanial drug susceptibility","authors":"Rokaya Ahmad ,&nbsp;Gaia Gastoldi ,&nbsp;Sin-Ting Wong ,&nbsp;Alvaro Baeza Garcia ,&nbsp;Guy Caljon","doi":"10.1016/j.ijpddr.2026.100632","DOIUrl":"10.1016/j.ijpddr.2026.100632","url":null,"abstract":"<div><div>Leishmaniasis is a major neglected tropical disease, exists in 98 countries and constitutes a global public health threat. As chemotherapy is confronted with drug resistance and treatment failure, understanding the underlying mechanisms and continued drug discovery efforts are needed in the fight against leishmaniasis. A previous cosmid-based overexpression study suggested a role for EamA (LINF_020008400), annotated as a putative drug-metabolite transporter, in resistance to novel antileishmanial oxaboroles. To assess fitness cost and drug susceptibility, gene deficient <em>Leishmania infantum</em> lines were generated using CRISPR-Cas9 gene editing and overexpression from the <em>ssu</em> locus was achieved using the pLEXSY system. While <em>in vitro</em> parasite growth and survival were unchanged compared to control lines, the intracellular burden of the null mutant was lower. <em>In vitro</em> exposure to current antileishmanial drugs and several novel leads revealed an unchanged drug sensitivity profile in extracellular and intramacrophage assays. Similarly, the overexpression lines showed a significantly lower infection rate, but their drug susceptibility profiles showed no significant differences from the control. Collectively, these data suggest that -under the tested conditions- LINF_020008400 is not essential for parasite fitness, host cell infectivity and survival following exposure to antiparasitic drugs.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100632"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922183","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":"Meclonazepam sensitivity of parasitic flatworms correlates with TRPMMCLZ sensitivity to meclonazepam","authors":"Claudia M. Rohr ,&nbsp;Paul McCusker ,&nbsp;Marc Kaethner ,&nbsp;Rebecca Armstrong ,&nbsp;Emily Robb ,&nbsp;Sang-Kyu Park ,&nbsp;Daniel J. Sprague ,&nbsp;Aaron G. Maule ,&nbsp;Mostafa Zamanian ,&nbsp;Britta Lundström-Stadelmann ,&nbsp;John D. Chan ,&nbsp;Jonathan S. Marchant","doi":"10.1016/j.ijpddr.2026.100634","DOIUrl":"10.1016/j.ijpddr.2026.100634","url":null,"abstract":"<div><div>The ionotropic portfolio of parasitic flatworms affords considerable opportunity for development of new anthelmintics. In this regard, transient receptor potential ion channels (TRP channels), cation channels responsive to various physiochemical cues, have emerged as promising druggable targets. This is based on the recent discovery that two members of a TRP channel subfamily (TRP melastatin or TRPM channels) are selectively activated by the clinical drug praziquantel (TRPM_PZQ), or the anthelmintic benzodiazepine meclonazepam (TRPM_MCLZ). Here, the efficacy of meclonazepam was investigated in a trematode (the liver fluke, <em>Fasciola hepatica</em>) and a cestode (<em>Echinococcus multilocularis</em>) model, in which an observed lack of meclonazepam sensitivity correlated with the lack of efficacy of meclonazepam on TRPM_MCLZ in these different parasites. Such correlations support assignment of TRPM_MCLZ as the meclonazepam target. Bioinformatic analysis of all available parasitic flatworm genomes allowed prediction of the meclonazepam binding pocket in over sixty different TRPM_MCLZ orthologs. Mutagenesis and functional profiling analyses highlighted the importance of a key residue in the S4 transmembrane helix of TRPM_MCLZ that impacts meclonazepam potency and efficacy. Variation of this residue and overall binding pocket architecture between different parasitic flatworm TRPM_MCLZ orthologs restricts meclonazepam action to a subset of schistosome species.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"30 ","pages":"Article 100634"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022785","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":"2025-12-01","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}