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

{"title":"Global equine parasite control guidelines: Consensus or confusion?","authors":"Martin K. Nielsen ,&nbsp;Alison Pyatt ,&nbsp;Jodie Perrett ,&nbsp;Eva Tydén ,&nbsp;Deborah van Doorn ,&nbsp;Tina H. Pihl ,&nbsp;Jennifer S. Schmidt ,&nbsp;Georg von Samson-Himmelstjerna ,&nbsp;Anne Beasley ,&nbsp;Ghazanfar Abbas ,&nbsp;Abdul Jabbar","doi":"10.1016/j.ijpddr.2025.100600","DOIUrl":"10.1016/j.ijpddr.2025.100600","url":null,"abstract":"<div><div>Equine parasite control has historically been characterized by confusing and conflicting information, posing significant challenges for veterinarians and horse owners to make evidence-based decisions. Since 2012, equine parasite control guidelines have been developed and published for different parts of the world to address this situation and provide trusted sources of current guidance. At the 2024 International Equine Infectious Disease Conference in Deauville, Normandy, France, lead authors of equine parasite control guideline documents published in the USA, UK, Sweden, Denmark, the Netherlands, Australia, and Europe convened and presented their guidelines. This led to a discussion of differences and similarities between the guidelines and an effort to identify current research needs in this area. In general, all guidelines recommend a surveillance-based approach for equine parasite control, emphasizing the importance of anthelmintic resistance testing. Some guidelines have a focus on controlling <em>Strongylus vulgaris</em>, while others primarily focus on cyathostomins, ascarids and tapeworms. Although the same four anthelmintic drug classes are marketed in most countries, there are some differences between product portfolios available, most notably between Australia and other countries. European countries have various degrees of prescription-only restrictions on anthelmintic products, whereas products are available over the counter in Australia and the USA. Commercially available diagnostic portfolios differed somewhat between countries and affected recommendations made as well. In conclusion, the guidelines are in general agreement and are based on the same general principles. One major challenge is communicating the recommendations effectively to end-users, which should be made a priority going forward.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100600"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212083","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":"Three Asparagine insertions in the K13-propeller led to Plasmodium falciparum becoming resistant to multiple antimalarial drugs","authors":"Zheng Xiang ,&nbsp;Mengxi Duan ,&nbsp;Siqi Wang ,&nbsp;Hui Zhao ,&nbsp;Wei Zhao ,&nbsp;Xiaosong Li ,&nbsp;Xinxin Li ,&nbsp;Weilin Zeng ,&nbsp;Yanrui Wu ,&nbsp;Fuxue Yang ,&nbsp;Xinyu Liu ,&nbsp;Cong Tang ,&nbsp;Liwang Cui ,&nbsp;Zhaoqing Yang","doi":"10.1016/j.ijpddr.2025.100590","DOIUrl":"10.1016/j.ijpddr.2025.100590","url":null,"abstract":"<div><div>Drug resistance in <em>Plasmodium falciparum</em> represents a significant challenge in malaria treatment. Identifying the molecular markers associated with <em>P. falciparum</em> resistance will effectively detect resistance and enhance treatment efficiency. In this study, we utilized the advanced CRISPR/Cas9 technology to precisely insert one, two, or three asparagine residues into the Kelch 13(K13) gene of the 3D7 strain, positioned after the 142nd amino acid residue, resulting in 1N-3D7, 2N-3D7, and 3N-3D7. Using ring-stage survival assays (RSA), drug sensitivity evaluations, and in vitro developmental assessments, our findings revealed a trend: 1) the insertion of asparagine residues into the parasite genome increased RSA, with more asparagine insertions leading to higher RSA. 2) According to the IC50 values, 1N-3D7 and 2N-3D7 exhibited similar sensitivity profiles across all ten tested drugs, with both demonstrating resistance to Naphthoquine, indicating that the insertions of one or two asparagines played an equivalent role in conferring resistance. However, the insertion of three asparagine residues resulted in significantly higher IC50 values compared to the first two forms when tested with Artesunate, Artemether, Dihydroartemisinin, Pyronaridine Phosphate, and Naphthoquine, showing resistance to all five drugs. Furthermore, 3N-3D7 exhibited a prolonged ring phase and a shortened trophozoite phase within red blood cells; the schizont phase appeared synchronous with the others, yet its mature schizonts contained fewer merozoites. Additionally, 3N-3D7 exhibited a fitness defect, with the proportion decreasing gradually during co-culture with 3D7, its fitness cost calculated as 14.88 ± 2.87. All these results support the opinion that the insertion of three asparagines was a molecular marker of resistance to artemisinin derivatives, Pyronaridine Phosphate, and Naphthoquine in <em>P. falciparum.</em></div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100590"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204746","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":"gdSir2.1 and gdSir2.3 are involved in albendazole resistance in Giardia duodenalis via regulation of the oxidative stress response","authors":"Adrián Chávez-Cano ,&nbsp;Scott C. Dawson ,&nbsp;M. Guadalupe Ortega-Pierres","doi":"10.1016/j.ijpddr.2025.100596","DOIUrl":"10.1016/j.ijpddr.2025.100596","url":null,"abstract":"<div><div>Albendazole resistance in <em>Giardia duodenalis</em> includes a complex and multifactorial challenge that potentially involves non-reported pathways such as the participation of metabolic regulators. In this context, sirtuins, known as metabolic sensors in various cellular processes, have emerged as promising candidates for novel anti-parasitic treatments. To investigate their role in albendazole (ABZ) resistance, initially we analyzed the expression of sirtuins in three <em>Giardia</em> strains resistant to 8 μM, 1.5 μM and 250 μM of ABZ that were obtained in our laboratory. Additionally, we used a CRISPRi-based knockdownstrategy to repress several sirtuins in <em>Giardia</em> and analyzed the effect of sirtuins on ABZ resistance. Our findings demonstrated a significant upregulation of sirtuins gdSir2.1, gdSir2.2 and gdSir2.3 in the three distinct albendazole-resistant lines. Knockdown of gdSir2.1 and gdSir2.3 resulted in heightened parasite susceptibility to both albendazole and hydrogen peroxide. Further, our study suggested that sirtuins contribute to the regulation of reactive oxygen species (ROS) levels, oxidative DNA damage, and the expression of oxidative stress response (OSR) genes within the parasite. Collectively, our results demonstrated that gdSir2.1 and gdSir2.3 play a significant role in mediating albendazole resistance, primarily through regulating the oxidative stress response.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100596"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947607","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":"Effect of urea and squaramide IMPDH inhibitors on C. parvum: in vitro trial design impacts the assessment of drug efficacy","authors":"Anne-Charlotte Lenière ,&nbsp;Amit Upadhyay ,&nbsp;Jérôme Follet ,&nbsp;Timothy P. O'Sullivan","doi":"10.1016/j.ijpddr.2025.100592","DOIUrl":"10.1016/j.ijpddr.2025.100592","url":null,"abstract":"<div><div>The protozoan parasite <em>Cryptosporidium</em> is the etiological agent of cryptosporidiosis, a ubiquitous diarrheic disease affecting humans and animals. Treatment options are limited, highlighting an urgent need for novel therapeutics. Despite decades of research and a wide diversity of strategies to tackle parasite metabolic pathways, no completely effective drug has been identified to date. Within targeted parasite enzymatic and metabolic pathways, the synthesis of nucleotide mediated by the inosine 5′-monophosphate dehydrogenase (IMPDH) enzyme is the focus of significant research efforts. Based on our prior studies of bacterial IMPDH inhibitors, we report herein the development and characterisation of novel inhibitors targeting <em>Cryptosporidium parvum</em> IMPDH (<em>Cp</em>IMPDH). Specifically, we synthesised heteroaryl-containing urea and squaramide analogues to evaluate their potential <em>in vitro</em> anti-<em>Cryptosporidium</em> activity. Initial screening identified nine active compounds with the most potent candidates achieving IC₅₀ values as low as 2.2 μM. Subsequent time-course experiments revealed that the molecules effectively inhibit parasite invasion and early intracellular development but failed to tackle <em>C. parvum</em> growth when introduced at 30 h post infection. The present work introduces a new family of squaramide-derived IMPDH inhibitors and also interrogates the need to standardise commonly accepted protocols used for assessing anti-cryptosporidial drug activity.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100592"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898678","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":"New derivatives of benzhydroxamic acid with nematocidal activity against Haemonchus contortus and Caenorhabditis elegans","authors":"Josef Krátký ,&nbsp;Markéta Zajíčková ,&nbsp;Aya C. Taki ,&nbsp;Oliver Michel ,&nbsp;Petra Matoušková ,&nbsp;Ivan Vokřál ,&nbsp;Karolína Štěrbová ,&nbsp;Ondřej Vosála ,&nbsp;Beate Lungerich ,&nbsp;Thomas Kurz ,&nbsp;Robin B. Gasser ,&nbsp;Karel Harant ,&nbsp;Lenka Skálová","doi":"10.1016/j.ijpddr.2025.100599","DOIUrl":"10.1016/j.ijpddr.2025.100599","url":null,"abstract":"<div><div>Parasitic nematodes cause a wide range of diseases in animals, including humans. However, the efficacy of existing anthelmintic drugs, commonly used to treat these infections, is waning due to the increasing prevalence of drug resistance in nematode populations. This growing challenge underscores the urgent need to discover and develop novel nematocidal drugs that target new molecular pathways. In the present study, 13 novel derivatives of benzhydroxamic acid (OMKs) were designed and synthesized. Their anthelmintic activity was tested in the parasitic nematode <em>Haemonchus contortus</em> (barber's pole worm) and the free-living nematode <em>Caenorhabditis elegans</em> and potential toxicity assessed in mammalian models. Compound OMK211 showed the most promising results. It decreased viability and motility of larval and adult stages of both nematode species and of both drug-sensitive and drug-resistant strains of <em>H. contortus</em> at micromolar concentrations with the highest efficacy in <em>H. contortus</em> adult males (IC₅₀ ∼ 1 μM). Moreover, OMK211 was not toxic in mammalians cells <em>in vitro</em> and in mice <em>in vivo</em>. Consequently, thermal proteome profiling analysis was used to infer the putative molecular target of OMK211 in <em>H. contortus</em>. The results revealed C2-domain containing protein A0A6F7Q0A8, encoded by gene HCON_00184,900, as an interacting partner of OMK211. Using advanced structural prediction and docking tools, this protein is considered an interesting putative molecular target of new nematocidal drugs as its orthologs are present in several nematodes but not in mammals. In conclusion, novel derivatives of benzhydroxamic acid represent a promising new class of potential anthelmintics, which deserve further testing.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100599"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125291","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":"Ursolic acid induces apoptosis and disrupts host-parasite interactions in Theileria annulata-infected cells","authors":"Sakshi Singh ,&nbsp;Madhusmita Subudhi ,&nbsp;Vengatachala Moorthy A ,&nbsp;Akash Suresh ,&nbsp;Paresh Sharma","doi":"10.1016/j.ijpddr.2025.100593","DOIUrl":"10.1016/j.ijpddr.2025.100593","url":null,"abstract":"<div><div>This study explores the anti-proliferative and anti-parasitic properties of ursolic acid (UA) in <em>Theileria annulata</em>-infected bovine (TA) cells. Dose-response analyses determined an IC₅₀ value of approximately 5 μg/mL for UA, demonstrating selective cytotoxicity toward infected cells with minimal impact on healthy cells. UA treatment induced pronounced morphological alterations and apoptosis in TA cells, as evidenced by light microscopy and a time-dependent increase in cell mortality. Notably, UA exhibited consistent efficacy against both buparvaquone (BPQ)-sensitive and BPQ-resistant TA cell lines, highlighting its broad-spectrum anti-parasitic potential. Mechanistic investigations revealed that UA triggers DNA damage, elevates reactive oxygen species (ROS) levels, disrupts mitochondrial function, and induces sub-G1 phase arrest, culminating in apoptosis primarily via the intrinsic pathway. Mass spectrometry-based proteomic profiling identified significant perturbations in host cell pathways, including DNA repair mechanisms, cell cycle regulation, and signaling networks, alongside direct interference with parasite metabolic processes. Western blot analysis further confirmed UA-mediated modulation of host cell signaling pathways and chromatin organization. Given the rising incidence of drug-resistant <em>T. annulata</em> strains, the development of novel therapeutic strategies is imperative. These findings highlight UA's multifaceted mechanism of action, targeting both parasitic and host cellular processes, and position it as a promising candidate for the treatment of bovine theileriosis.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100593"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860023","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":"2025-08-01","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":"High frequency of benzimidazole resistance polymorphisms and age-class differences in trichostrongyle nematodes of ranched bison from the south-central United States","authors":"Kaylee R. Kipp ,&nbsp;Elizabeth M. Redman ,&nbsp;Joe L. Luksovsky ,&nbsp;Dani Claussen ,&nbsp;John S. Gilleard ,&nbsp;Guilherme G. Verocai","doi":"10.1016/j.ijpddr.2025.100594","DOIUrl":"10.1016/j.ijpddr.2025.100594","url":null,"abstract":"<div><div>Bison production is a growing sector of the United States agriculture, with more consumers choosing bison products. Commercial bison are kept on smaller pastures and treated with anthelmintics for gastrointestinal nematodes (GIN) to maintain production. However, there is a lack of information regarding the GIN parasite communities in ranched bison or the extent of their resistance to anthelmintics. Our objectives were: i) to determine the GIN species present and the extent of resistance to the benzimidazole drug class in commercial bison herds in the southern US and ii) to assess age class differences in GIN species composition and BZ resistance. Composite coprocultures from bison in Texas (<em>n</em> = 14) and Oklahoma (<em>n</em> = 2), and individual bison of different age classes from a single ranch in central Texas (<em>n</em> = 43) were analyzed using ITS2 rDNA nemabiome metabarcoding to determine the trichostrongylid species composition. For both the composite and individual samples, the most common trichostrongylid species found were <em>Haemonchus contortus, Haemonchus placei</em>, and <em>Ostertagia ostertagi</em>. Among the known canonical isotype-1 β-tubulin BZ resistance polymorphisms (at codons 200, 198, 167), the 200Y (TTC &gt; T<u>A</u>C) substitution was the most widespread across the two southern states, with a prevalence of 81.3 %. Other polymorphisms, such as 167Y (TTC &gt; T<u>A</u>C) and 198L (GAA &gt; <u>TT</u>A), were also detected, and both had prevalences of 62.5 %. <em>Ostertagia ostertagi</em> was found to have very high frequencies (overall mean frequency = 62.6 %; range = 28.3–100 %) of the 200Y (TTC &gt; T<u>A</u>C) polymorphism in all age classes sampled. Overall, benzimidazole resistance polymorphisms were found at moderate to high frequency in the three major economically important GIN species in ranched bison in Texas and Oklahoma, suggesting a potential widespread distribution of benzimidazole resistance polymorphisms in the southern United States. This work has important implications for all other grazing livestock and illustrates the importance of early detection of anthelmintic resistance and the need for mitigation strategies.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100594"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838341","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":"Metabolomics study of 3-O-p-(Z/E)-coumaroyltormentic acid-treated Trypanosoma brucei brucei","authors":"Lúcia Mamede ,&nbsp;Fanta Fall ,&nbsp;Madeline Vast ,&nbsp;Kristelle Hughes ,&nbsp;Giorgia Martelli ,&nbsp;Francesco Caligiore ,&nbsp;Bernadette Govaerts ,&nbsp;Paul A.M. Michels ,&nbsp;Michel Frédérich ,&nbsp;Joëlle Quetin-Leclercq","doi":"10.1016/j.ijpddr.2025.100595","DOIUrl":"10.1016/j.ijpddr.2025.100595","url":null,"abstract":"<div><div>Trypanosomiasis is a parasitic disease for which new treatments are needed due to the frequent occurrence of adverse side effects of current available drugs. Natural compounds found in traditionally used plants offer opportunities to discover innovative compounds that could prove pivotal to antitrypanosomal drug development. 3-O-<em>p</em>-(<em>Z/E</em>)-coumaroyltormentic acids (CTA) were isolated first from the West Africa-native tree <em>Vitellaria paradoxa</em> and have demonstrated quite selective <em>in vitro</em> and <em>in vivo</em> antitrypanosomal activity, despite the unknown mode of action. In this study, a metabolomics analysis using the data from both LC-HR-MS and ¹H-NMR described CTA's effects on <em>Trypanosoma brucei</em> after 3 h exposure under 5 or 10 x EC₅₀. Our study shows CTA's activity impacted tryptophan metabolism and reveals potential targets in different branches of this metabolism. Our results demonstrate a likely presence of enzymes dedicated to tryptophan, like a tryptophan aminotransferase, tryptophan 2,3-dioxygenase and/or indoleamine 2,3-dioxygenase, and other enzymes of the kynurenine pathway, despite the absence of their description thus far in this species. These data further implicate that CTA's toxic effect on the tryptophan metabolism may be attributed to the decrease of the intracellular level of essential aspartate, resulting from inhibition of its aminotransferase. In resume, our study shines light on the likelihood of the tryptophan metabolism pathway presenting innovative targets toward the development of antitrypanosomal drugs. These require confirmation through functional and enzymatic studies.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100595"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070138","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":"Type A asparagine synthetase in the zoonotic Cryptosporidium parvum (CpAsnA): Biochemical features and potential as a novel therapeutic target","authors":"Zongzhen Zhai ,&nbsp;Peng Jiang ,&nbsp;Dongqiang Wang,&nbsp;Tao Chen,&nbsp;Jigang Yin,&nbsp;Guan Zhu","doi":"10.1016/j.ijpddr.2025.100601","DOIUrl":"10.1016/j.ijpddr.2025.100601","url":null,"abstract":"<div><div><em>Cryptosporidium parvum</em> is an intestinal protozoan parasite, the causative agent of the diarrheal cryptosporidiosis in humans and animals for which fully effective treatments are yet unavailable. The <em>C. parvum</em> genome encodes highly streamlined metabolic pathways, lacking enzymes to synthesize any amino acids de novo. However, it possesses a standalone type A asparagine synthetase (CpAsnA) that catalyzes the ammonia/ATP-dependent synthesis of asparagine from aspartate. Here, we expressed recombinant CpAsnA and characterized its enzyme functional parameters towards aspartate. We screened 5000 bioactive compounds using a thermal shift assay (TSA) and identified 31 hits showing high binding affinity to CpAsnA. Four of the 31 TSA hits exhibited lower micromolar activity against CpAsnA enzyme activity, including XD14, SB225002, histone acetyltransferase inhibitor II (HATi-II) and tolcapone. Among the four CpAsnA inhibitors, three displayed lower micromolar in vitro efficacy against the growth of <em>C. parvum</em> in vitro with satisfactory selectivity indices as primary antiparasitic hits. Our data suggest that CpAsnA merits further investigation as a potential drug target in the parasite.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100601"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144240855","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}