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

{"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}

{"title":"Promising efficacy of nitrogen-containing bisphosphonates against the infection of Cryptosporidium spp.","authors":"Wenyan Hou, Xinyi Chen, Yingying Zhang, Longfei Wu, Songying Sun, Jiaye Guo, Wenchao Zhao, Junqiang Li, Sumei Zhang, Longxian Zhang, Xiaoying Li","doi":"10.1016/j.ijpddr.2025.100607","DOIUrl":"10.1016/j.ijpddr.2025.100607","url":null,"abstract":"<p><p>Cryptosporidiosis is a major diarrheal disease that affects both humans and animals. Fully effective drug for treating cryptosporidiosis is still lacking. Nitrogen-containing bisphosphonates have been reported to inhibit Cryptosporidium growth in vitro; however, the in vivo efficacy against Cryptosporidium remain unevaluated. This study determined the anti-Cryptosporidium effect of three nitrogen-containing bisphosphonates risedronate, ibandronate, and zoledronate through both in vitro and in vivo experiments. It was determined that risedronate exhibited the highest therapeutic index of 39.10 among the three compounds, with the median effective concentration low to 17.44 μM against Cryptosporidium parvum infection in vitro. In vivo experiments showed that the high dose (10 mg/kg/d) of risedronate and ibandronate significantly reduced the shedding of Cryptosporidium tyzzeri oocyst, with no toxicity in ICR mice. Histopathological examinations of ICR mice indicated that high and medium (2 mg/kg/d) doses of the bisphosphonates could reduce intestinal damage, recover the height of intestinal villi and crypt depth, led to more intact intestinal structures, and risedronate showed the most promising effects. Furthermore, the three compounds modulated the elevated levels of IL-2, IL-4, and TNF-α cytokines, induced by C. tyzzeri infection, towards normalcy in a dose-dependent manner. In conclusion, the efficacy of three nitrogen-containing bisphosphonates against the in vitro and in vivo infection of Cryptosporidium spp. was assessed. Risedronate show promising effect for further development of new anticryptosporidial drugs.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"100607"},"PeriodicalIF":3.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812014","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":"Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites","authors":"Maria R. Gancheva ,&nbsp;Emma Y. Mao ,&nbsp;Ornella Romeo ,&nbsp;Daniel Vuong ,&nbsp;Ryan O'Handley ,&nbsp;Stephen W. Page ,&nbsp;Ernest Lacey ,&nbsp;Danny W. Wilson","doi":"10.1016/j.ijpddr.2025.100606","DOIUrl":"10.1016/j.ijpddr.2025.100606","url":null,"abstract":"<div><div>Frontline drug treatments for malaria are at risk of failing due to emerging resistance, meanwhile drugs used to treat toxoplasmosis have suboptimal efficacy and safety. As demonstrated by the success of clinically used antiparasitic drugs, the diverse structural complexity and biological activity of natural products holds great potential for drug discovery and development, to address the need for new compounds with novel mechanisms. Here we screened the BioAustralis Discovery Plates Series I library, a collection of 812 microbial natural product compounds including rare microbial metabolites, against <em>Plasmodium falciparum</em> erythrocytic stage and <em>Toxoplasma gondii</em> tachyzoite parasites. We identified 219 compounds that inhibited <em>P. falciparum</em> growth by at least 80 % at a concentration of 2 μg/mL (1–10 μM for &gt;90 % of compounds), whilst 149 compounds demonstrated equivalent activity against <em>T. gondii</em>. The active compounds were assigned based on chemical structure to more than 50 compound classes. After triaging active compounds for those with low mammalian cytotoxicity, we defined the <em>in vitro</em> half maximal inhibitory concentration (IC₅₀) of a selection of compounds against the parasites, identifying four compound groups with activity in the low nanomolar range. The macrocyclic lactone pladienolide B and cryptopleurine were found to be very potent against the parasites but also mammalian cells, warranting further structure-activity relationship investigation. Two groups, the monocyclic thiazole peptides, including micrococcin P1 and the thiocillins, and the pleuromutilins, exhibited both low antiparasitic IC₅₀ and low cytotoxicity, highlighting their potential for further analysis. This study defines the activity of the BioAustralis Discovery Plates Series I against two apicomplexan parasites of significant global importance, providing potential new tools to study parasite biology and possible starting points for novel antiparasitic development.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"Article 100606"},"PeriodicalIF":3.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surveillance of single nucleotide polymorphisms correlated to macrocyclic lactone resistance in Dirofilaria immitis from client-owned dogs across the United States.","authors":"Emily Curry, David Tack, Jessica Rodriguez, Danielle Brehm-Lowe, John Letherer, Megan Lineberry, Roger Prichard, Tobias Clark","doi":"10.1016/j.ijpddr.2025.100604","DOIUrl":"10.1016/j.ijpddr.2025.100604","url":null,"abstract":"<p><p>Dirofilaria immitis is a parasitic filarial nematode and the causative agent of heartworm disease in canids and other species. Heartworm disease is predominantly managed via macrocyclic lactone (ML) - based chemoprophylactics. Through opportunistic sampling, genotypically and phenotypically confirmed ML-resistant D. immitis isolates have been isolated in the Lower Mississippi River Valley region (LMRV); however, the pervasiveness of resistant isolates in the USA has not been evaluated. This study aimed to evaluate the geographic distribution and prevalence of genotypically ML-resistant heartworms in client-owned dogs across the USA over a 3-year period. Owner consent was obtained to collect microfilaremic blood samples from heartworm-positive dogs from participating clinics. Veterinarians completed a questionnaire on the known history of each dog, including treatment and travel history. A total of 310 microfilaremic blood samples were collected from 45 geographically diverse veterinary clinics located in 22 states. Microfilariae were filtered from blood, DNA extracted utilizing the QIAGEN QIAamp DNA Micro Kit and samples sequenced by the Génome Québec Innovation Centre to determine allele frequencies at nine SNP sites previously correlated with ML resistance. The highly predictive 2-SNP model was used to identify genotypically susceptible, mixed, and resistant populations. Computational analysis indicated 111 (35.8 %) were genotypically susceptible, 96 (31.0 %) were genotypically resistant, and 103 (33.2 %) were genotypically mixed. The genotypically mixed and ML-resistant infections were located within and outside of the endemic LMRV, as far north as Michigan, which indicates canine populations outside of the LMRV are at increased risk for transmission of potentially ML-resistant heartworm infections than previously hypothesized. Veterinary practitioners across the USA need to be aware of the potential risks of ML resistance heartworm infections and ensure patient compliance with recommended prevention protocols.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"29 ","pages":"100604"},"PeriodicalIF":3.4,"publicationDate":"2025-08-05","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":"Mechanistic, in-silico and in vitro studies with nitrofurans reveal potent leishmanicidal activity and inhibition of trypanothione reductase","authors":"Julia Andrés-Rodríguez ,&nbsp;María-Cristina González-Montero ,&nbsp;Nerea García-Fernández ,&nbsp;Juan-José Galano-Frutos ,&nbsp;Maria-Cristina de Rosa ,&nbsp;Patricia Ferreira ,&nbsp;María-Yolanda Pérez-Pertejo ,&nbsp;Rosa M. Reguera ,&nbsp;Rafael Balaña-Fouce ,&nbsp;Carlos García-Estrada","doi":"10.1016/j.ijpddr.2025.100605","DOIUrl":"10.1016/j.ijpddr.2025.100605","url":null,"abstract":"<div><div>Visceral leishmaniasis caused by <em>Leishmania infantum</em> and <em>Leishmania donovani</em> is one of the neglected tropical diseases (NTDs) caused by trypanosomatids with treatment options limited to outdated drugs often causing adverse effects and promoting drug resistance. Previous antileishmanial drug discovery campaigns have identified nitroheterocyclic molecules with high efficacy and a high selectivity index. Therefore, we have evaluated on our screening platform of fluorescent <em>L. donovani</em> amastigotes, the antileishmanial activity of seven nitrofuran derivatives: furazolidone, nitrofurazone, nitrofurantoin, nifurtimox, 5-nitro-2-furaldehyde diacetate, PYZD-4409 and 5-nitro-2-furonitrile. These compounds showed good efficacy against axenic and intramacrophage amastigotes, most of them showing low cytotoxicity in mammalian cell lines. These nitrofuran derivatives induced reactive oxygen species production in axenic amastigotes and inhibited trypanothione reductase (TryR) either in uncompetitive or competitive manner, thus suggesting that their mechanism of action involves increased oxidative stress caused by an imbalance in redox metabolism. Furazolidone exhibited the most promising antileishmanial profile, and molecular docking analysis revealed consistency with the strongest TryR uncompetitive inhibitory effect, demonstrating its high affinity for an alternative binding site near the substrate (oxidized trypanothione) pocket. Docking results also highlighted PYZD-4409 as the compound with the highest binding affinity, and showed consistency with its competitive inhibition mechanism. Furthermore, similar binding modes identified across <em>L. donovani</em> TryR and other homologous proteins suggest the potential broad-spectrum activity of these nitrofuran derivatives, thus underscoring their importance as promising candidates for the development of novel antileishmanial therapies with broad-spectrum applications.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100605"},"PeriodicalIF":3.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772517","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 and metabolism of artemisinin (ART) in Plasmodium yoelii: ART-heme adduct as a potential biomarker for its resistance","authors":"Shanshan Du ,&nbsp;Kun Xu ,&nbsp;Zhaohua Liu ,&nbsp;Jie Xing","doi":"10.1016/j.ijpddr.2025.100603","DOIUrl":"10.1016/j.ijpddr.2025.100603","url":null,"abstract":"<div><h3>Background</h3><div><em>Plasmodium falciparum</em> in Southeast Asia and Africa is developing resistance to the antimalarial drug artemisinin (ART). In this study, the metabolite of ART in <em>P. yoelii</em> parasites was evaluated as a potential biomarker for its antimalarial activity as well as its resistance.</div></div><div><h3>Methods</h3><div>The induced strain of <em>P. yoelii</em> (i<em>Py</em>) was first established after long-time pressure of ART in <em>P. yoelii</em> (<em>Py</em>)-infected mice. The metabolic and pharmacokinetic profiles of ART were then studied in both <em>P. yoelii</em> parasites and infected mice. The pharmacokinetic-pharmacodynamic behaviors of ART in two strains of <em>P. yoelii</em> (<em>Py</em> and i<em>Py</em>) were compared. The pharmacokinetic parameters (<em>e.g</em>., AUC and C_max) of ART metabolite in parasites were normalized by infected RBC (iRBC) burden.</div></div><div><h3>Results</h3><div>Lower antimalarial activity was found for ART against i<em>Py</em> than <em>Py</em>, in terms of the 90 % growth inhibitory dose (ED₉₀, 2.9-fold). In contrast with <em>Py</em>, mice infected with i<em>Py</em> could survive for at least 28 days. When ART was orally given to (i)<em>Py</em>-infected mice, ART was detected in parasites as ART-heme adduct. The plasma clearance of ART was not affected by (i)<em>Py</em>-infection, and higher plasma clearance of ART (by 3-4-fold) was found after multiple doses. After being normalized by iRBC, the exposure of ART-heme in <em>P. yoelii</em> parasites was dose-dependent, and its maximum concentration (C_max) was reached at 3–5 h. Compared with <em>Py</em> parasites, lower iRBC-normalized exposure of ART-heme (AUC_{0-t, normalized}) was found in i<em>Py</em> parasites (61.1 % of <em>Py</em> parasites) after an oral dose of ART to infected mice.</div></div><div><h3>Conclusions</h3><div>Plasma ART concentration merely reflected drug exposure in the host. ART-heme adduct was the major metabolite for ART in <em>P. yoelii</em> parasites, and it could be a potential biomarker for the antimalarial activity of ART as well as its resistance.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100603"},"PeriodicalIF":4.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614213","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":"Antimalarial drug resistance and drug discovery: learning from the past to innovate the future","authors":"Liana Theodoridis,&nbsp;Teresa G. Carvalho","doi":"10.1016/j.ijpddr.2025.100602","DOIUrl":"10.1016/j.ijpddr.2025.100602","url":null,"abstract":"<div><div>The emergence and spread of artemisinin-resistant malaria over the past 15 years has led to a recent rise in global malaria cases and represents a major public health concern. Following decades of intense research efforts, the first malaria vaccine has been approved for clinical use in October of 2021. However, its 36 % efficacy highlights the ongoing need for novel and effective drugs to combat malaria. The majority of current antimalarials are derivatives of previous efficient compounds whilst new treatments with diverse chemical scaffolds have not been implemented into clinical practice since 1996. We argue that current research efforts should focus on developing novel chemical classes of compounds to help fight drug resistant malaria. Here we provide a comprehensive review of the antimalarial treatments currently in clinical use and discuss their significant limitations due to parasite drug resistance. Further, we discuss various approaches to antimalarial drug discovery and offer new perspectives on the topic, informing on current methods, both rarely and extensively used. Collating the most recent and up-to-date drug discovery strategies will not only maximise current global research efforts but will ensure all possible drug development avenues are trialed. This review provides innovative insights to circumvent antimalarial drug resistance and diversify malaria therapeutics.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100602"},"PeriodicalIF":4.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144653272","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}