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

{"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":"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}

{"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":"Tartrolon E rapidly blocks Toxoplasma gondii capacity to invade host cells","authors":"Fernanda G. Fumuso ,&nbsp;Jason A. Clement ,&nbsp;Matthew J. Todd ,&nbsp;Roberta M. O'Connor","doi":"10.1016/j.ijpddr.2025.100591","DOIUrl":"10.1016/j.ijpddr.2025.100591","url":null,"abstract":"<div><div>Toxoplasmosis is a worldwide parasitic disease caused by the apicomplexan <em>Toxoplasma gondii</em>. Severe neurological illness occurs in immunosuppressed patients, and congenital disorders can follow transplacental primo infection during pregnancy. New effective antiparasitic drugs are needed since chronic cystic stages are resistant to current available treatments, and some of the congenital infections are unresponsive to available therapeutics. Tartrolon E (trtE) is a marine secondary metabolite that has high selectivity against human and animal apicomplexan parasites including <em>T. gondii</em>, <em>Cryptosporidium parvum</em> and <em>Plasmodium falciparum</em>. We evaluated the effect of the compound on extracellular tachyzoite viability, morphology, membrane permeability and its ability to block host cell attachment and/or invasion. While 80 % of <em>T. gondii</em> infective capacity is blocked after only 30 min of compound treatment, parasite viability, morphology, membrane integrity and host cell attachment were unaffected until after 4 h of treatment. These effects were irreversible when parasites were allowed to infect host cells after trtE treatment. Drug exposure for more than 4 h significantly affected tachyzoite survival and altered parasite morphology. The mechanism of action of trtE is still unknown but includes blocking parasite invasion processes. Further research is needed to determine the molecular target of trtE to further progress the compound as an antiparasitic candidate.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100591"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143830062","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":"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":"Resistance to apicoplast translational inhibitors in Plasmodium","authors":"Jessica L. Home,&nbsp;Geoffrey I. McFadden,&nbsp;Christopher D. Goodman","doi":"10.1016/j.ijpddr.2025.100597","DOIUrl":"10.1016/j.ijpddr.2025.100597","url":null,"abstract":"<div><div>The spread of drug-resistant <em>Plasmodium</em> threatens malaria control efforts. Thus, understanding the mechanisms of resistance is crucial for implementing effective treatments and prevention strategies. The prokaryote-like translational machinery encoded by the apicoplast is the apparent target of several antibiotics with antimalarial activity. Among them, doxycycline and clindamycin are widely used for malaria treatment and/or chemoprophylaxis. However, the mechanisms underlying <em>Plasmodium</em> resistance to apicoplast-targeting antibiotics, and the evolution of such resistance mechanisms, remain largely unknown. In this review, we summarise reported cases of resistance to apicoplast translational inhibitors uncovered in either laboratory or clinical settings. We highlight the potential evolutionary pathway of doxycycline resistance, explore why resistance to these antibiotics remains rare in the field, and assess whether expanding their use in malaria treatment and prevention is a viable strategy.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"28 ","pages":"Article 100597"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070137","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":"2025-08-01","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}

{"title":"Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus","authors":"Autumn Collins ,&nbsp;Sierra Varley ,&nbsp;Tobias Clark ,&nbsp;Nathan Chubb ,&nbsp;Sean Forrester ,&nbsp;Jean-Paul Desaulniers","doi":"10.1016/j.ijpddr.2025.100587","DOIUrl":"10.1016/j.ijpddr.2025.100587","url":null,"abstract":"<div><div>The acetylcholine-gated chloride channel (ACC) family in parasitic nematodes represents a promising target for anthelmintic drug development. Levamisole, a widely known and utilized cholinergic agonist, has been used for decades to address many types of parasitic infections by targeting nematode nicotinic acetylcholine receptors (nAChRs) in nematodes. In this study, we report the synthesis and pharmacological evaluation of eight levamisole derivatives, five of which are novel, on the <em>H. contortus</em> ACC-2 receptor. This includes a CF₃-derivatized compound we have identified as compound <strong>6</strong> whose structure contains levamisole as a backbone with the addition of a 2-trifluoromethyl benzyl group. Electrophysiological assays revealed that compound <strong>6</strong> exhibited a five-fold increase in sensitivity (EC₅₀ 20 μM) compared to levamisole (EC₅₀ 100 μM), our parent compound, with an EC₅₀ comparable to that of acetylcholine (20 μM). Investigation of the <em>in silico</em> docking of compound <strong>6</strong> with <em>H. contortus</em> ACC-2 suggest that it interacts uniquely within the <em>H. contortus</em> ACC-2 binding pocket, which may contribute to its increased receptor sensitivity. These findings highlight the potential of structural modifications containing an electron-withdrawing group at the 2-position which can significantly enhance activity at the <em>H. contortus</em> ACC-2 receptor. This opens many avenues for the development of more effective treatments against parasitic nematodes, in an environment with increasing resistance.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100587"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562769","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":"Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women","authors":"Lucia Borrallo-Lopez ,&nbsp;Laura Guzman ,&nbsp;Noelia G. Romero ,&nbsp;Anna Sampietro ,&nbsp;Ana Mallo-Abreu ,&nbsp;Laia Guardia-Escote ,&nbsp;Elisabet Teixidó ,&nbsp;Burkhard Flick ,&nbsp;Xavier Fernàndez-Busquets ,&nbsp;Diego Muñoz-Torrero ,&nbsp;Marta Barenys","doi":"10.1016/j.ijpddr.2025.100582","DOIUrl":"10.1016/j.ijpddr.2025.100582","url":null,"abstract":"<div><h3>Background</h3><div>Malaria during pregnancy implies a high risk for the mother and the developing child. However, the therapeutic options for pregnant women have historically been very limited, especially during the first trimester of pregnancy due to potential adverse effects on embryo-fetal development. Recently, there has been great controversy regarding these potential embryo-fetal adverse effects because the results of rodent studies were not in accordance with the clinical data available, and finally the WHO has changed the recommendations for pregnant women with uncomplicated <em>P. falciparum</em> malaria to treatment with artemether-lumefantrine during the first trimester. The discrepancy between pre-clinical and clinical studies has been attributed to species-differences in the duration of the window of susceptibility of circulating primitive erythroblasts.</div></div><div><h3>Methods</h3><div>Here we provide a tool based on an alternative method to animal experimentation that accelerates the research of novel drugs for pregnant women. We have adapted the zebrafish embryo developmental toxicity assay to include hemoglobin staining in the embryos and two time-points of lethality and dysmorphogenesis evaluation. These two time-points were selected to include one when the development is independent of and one when the development is dependent of erythrocytes function. The method was used to test four marketed antimalarial drugs and three new antimalarial drug candidates.</div></div><div><h3>Results</h3><div>Our combination of tests can correctly predict the teratogenic and non-teratogenic effects of several antimalarial marketed drugs (artemisinin, quinine, chloroquine, and dihydroartemisinin + desbutyl-lumefantrine). Furthermore, we have tested three new drug candidates (GS-GUAN, DONE3TCl, and YAT2150) with novel mechanisms of action, and different from those of the marketed antimalarial drugs.</div></div><div><h3>Conclusions</h3><div>We propose a decision tree combining the results of the two time-points of evaluation together with the information on significant erythrocyte depletion. The aim of this decision tree is to identify compounds with no or lower hazard on teratogenicity or erythrocyte depletion at an early phase of the drug development process.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100582"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070871","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}