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

{"title":"Inhibition of Giardia duodenalis by isocryptolepine -triazole adducts and derivatives","authors":"Supaluk Popruk ,&nbsp;Jumreang Tummatorn ,&nbsp;Suthasinee Sreesai ,&nbsp;Sumate Ampawong ,&nbsp;Tipparat Thiangtrongjit ,&nbsp;Phornpimon Tipthara ,&nbsp;Joel Tarning ,&nbsp;Charnsak Thongsornkleeb ,&nbsp;Somsak Ruchirawat ,&nbsp;Onrapak Reamtong","doi":"10.1016/j.ijpddr.2024.100561","DOIUrl":"10.1016/j.ijpddr.2024.100561","url":null,"abstract":"<div><p><em>Giardia duodenalis</em>, a widespread parasitic flagellate protozoan causing giardiasis, affects millions annually, particularly impacting children and travellers. With no effective vaccine available, treatment primarily relies on the oral administration of drugs targeting trophozoites in the small intestine. However, existing medications pose challenges due to side effects and drug resistance, necessitating the exploration of novel therapeutic options. Isocryptolepine, derived from <em>Cryptolepis sanguinolenta</em>, has demonstrated promising antimicrobial and anticancer properties. This study evaluated eighteen isocryptolepine-triazole adducts for their antigiardial activities and cytotoxicity, with ISO2 demonstrating potent antigiardial activity and minimal cytotoxicity on human intestinal cells. Metabolomics analysis revealed significant alterations in <em>G. duodenalis</em> metabolism upon ISO2 treatment, particularly affecting phospholipid metabolism. Notably, the upregulation of phytosphingosine and triglycerides, and downregulation of certain fatty acids, suggest a profound impact on membrane composition and integrity, potentially contributing to the parasite's demise. Pathway analysis highlighted glycerophospholipid metabolism, cytochrome <em>b</em>5 family heme/steroid binding domain, and P-type ATPase mechanisms as critical pathways affected by ISO2 treatment, underscoring its importance as a potential target for antigiardial therapy. These findings shed light on the mode of action of ISO2 against <em>G. duodenalis</em> and provide valuable insights for further drug development. Moreover, the study also offers a promising avenue for the exploration of isocryptolepine derivatives as novel therapeutic agents for giardiasis, addressing the urgent need for more effective and safer treatment options.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100561"},"PeriodicalIF":4.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000423/pdfft?md5=cf1b4f8e64b6cac6a25597bf8c18ea7c&pid=1-s2.0-S2211320724000423-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991191","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":"Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products","authors":"Kuang-Yao Chen ,&nbsp;Chien-Ju Cheng ,&nbsp;Yuan-Ting Chang ,&nbsp;Yi-Hsuan Lin ,&nbsp;Yi-Hao Huang ,&nbsp;Sheng-Yu Lin ,&nbsp;Lian-Chen Wang ,&nbsp;Kai-Yuan Jhan ,&nbsp;Cheng-Hsun Chiu","doi":"10.1016/j.ijpddr.2024.100560","DOIUrl":"10.1016/j.ijpddr.2024.100560","url":null,"abstract":"<div><p>Autophagy is a vital cellular process responsible for digesting various cytoplasmic organelles. This process plays a crucial role in maintaining cell survival and homeostasis, especially under conditions that cause nutrient deficiency, cellular damage, and oxidative stress. Neuroangiostrongyliasis is an infection caused by the parasitic nematode <em>Angiostrongylus cantonensis</em> and is considered as an emerging disease in many parts of the world. However, effective therapeutic strategies for neuroangiostrongyliasis still need to be further developed. In this study, we investigated the effects of benzaldehyde treatment on autophagy and sonic hedgehog (Shh) signaling in <em>A. cantonensis-</em>infected mice and its mechanisms. First, we found autophagosome generation in the central nervous system after <em>A. cantonensis</em> infection. Next, benzaldehyde combined with albendazole treatment reduced eosinophilic meningitis and upregulated the expression of Shh signaling- and autophagy-related molecules in <em>A. cantonensis</em>-infected mouse brains. In vitro experiments demonstrated that benzaldehyde could induce autophagy via the Shh signaling pathway in <em>A. cantonensis</em> excretory-secretory products (ESPs)-treated mouse astrocytes. Finally, benzaldehyde treatment also decreased lipid droplet accumulation and increased cholesterol production by activating the Shh pathway after ESPs treatment. In conclusion, these findings suggested that benzaldehyde treatment could alleviate brain damage by stimulating autophagy generation through the Shh signaling pathway.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100560"},"PeriodicalIF":4.1,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000411/pdfft?md5=cf24b1d2bd7ceca652003c382746d431&pid=1-s2.0-S2211320724000411-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141985854","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":"Macrocyclic lactones and ectoparasites control in livestock: Efficacy, drug resistance and therapeutic challenges","authors":"A. Lifschitz ,&nbsp;S. Nava ,&nbsp;V. Miró ,&nbsp;C. Canton ,&nbsp;L. Alvarez ,&nbsp;C. Lanusse","doi":"10.1016/j.ijpddr.2024.100559","DOIUrl":"10.1016/j.ijpddr.2024.100559","url":null,"abstract":"<div><p>Macrocyclic lactones (MLs) are the cornerstone of parasite control in livestock due to their broad-spectrum activity against endo (nematodes) and ecto (lice, ticks, mites) parasites. These molecules, introduced into the veterinary pharmaceutical market 40 years ago, have substantially improved animal welfare and productivity by offering extended high efficacy, reducing treatment frequency, and displaying a favorable safety profile. However, their widespread and intensive use has led to a significant challenge nowadays: <em>the development of parasite resistance</em>. This review focuses on the critical link between drug pharmacokinetics (variation in concentration profiles and exposure over time) and pharmacodynamics (drug efficacy) and the ability of both avermectin and milbemycin MLs families to control livestock ectoparasites. This review discusses the integrated assessment of drug behavior in the host, its diffusion into target parasites, and the impact of different pharmaceutical formulations on enhancing drug delivery to infection sites. These are considered critical research/development areas to optimize the use of MLs, preventing treatment failures and finally extending the lifespan of these essential pharmaceutical ingredients. Finally, the importance of the rational use of MLs, guided by parasite epidemiology and pharmacological knowledge, is emphasized as a key strategy to preserve the antiparasitic efficacy of these still very useful molecules.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100559"},"PeriodicalIF":4.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221132072400040X/pdfft?md5=424f13767e5a50ca691d68edb050274c&pid=1-s2.0-S221132072400040X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916619","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":"A multiplexed high throughput screening assay using flow cytometry identifies glycolytic molecular probes in bloodstream form Trypanosoma brucei","authors":"Daniel H. Call ,&nbsp;John Asafo Adjei ,&nbsp;Ryan Pilgrim ,&nbsp;James W. Jeong ,&nbsp;E. Vance Willis ,&nbsp;Ronald A. Zegarra ,&nbsp;Nicholas L. Tapia ,&nbsp;Madalyn Osterhaus ,&nbsp;Jacob A. Vance ,&nbsp;Charles M. Voyton ,&nbsp;James A. Call ,&nbsp;Sabrina S. Pizarro ,&nbsp;James C. Morris ,&nbsp;Kenneth A. Christensen","doi":"10.1016/j.ijpddr.2024.100557","DOIUrl":"10.1016/j.ijpddr.2024.100557","url":null,"abstract":"<div><p>Kinetoplastid organisms, including <em>Trypanosoma brucei</em>, are a significant health burden in many tropical and semitropical countries. Much of their metabolism is poorly understood. To better study kinetoplastid metabolism, chemical probes that inhibit kinetoplastid enzymes are needed. To discover chemical probes, we have developed a high-throughput flow cytometry screening assay that simultaneously measures multiple glycolysis-relevant metabolites in live <em>T. brucei</em> bloodstream form parasites. We transfected parasites with biosensors that measure glucose, ATP, or glycosomal pH. The glucose and ATP sensors were FRET biosensors, while the pH sensor was a GFP-based biosensor. The pH sensor exhibited a different fluorescent profile from the FRET sensors, allowing us to simultaneously measure pH and either glucose or ATP. Cell viability was measured in tandem with the biosensors using thiazole red. We pooled sensor cell lines, loaded them onto plates containing a compound library, and then analyzed them by flow cytometry. The library was analyzed twice, once with the pooled pH and glucose sensor cell lines and once with the pH and ATP sensor cell lines. Multiplexing sensors provided some internal validation of active compounds and gave potential clues for each compound's target(s). We demonstrated this using the glycolytic inhibitor 2-deoxyglucose and the alternative oxidase inhibitor salicylhydroxamic acid. Individual biosensor-based assays exhibited a Z′-factor value acceptable for high-throughput screening, including when multiplexed. We tested assay performance in a pilot screen of 14,976 compounds from the Life Chemicals Compound Library. We obtained hit rates from 0.2 to 0.4% depending on the biosensor, with many compounds impacting multiple sensors. We rescreened 44 hits, and 28 (64%) showed repeatable activity for one or more sensors. One compound exhibited EC₅₀ values in the low micromolar range against two sensors. We expect this method will enable the discovery of glycolytic chemical probes to improve metabolic studies in kinetoplastid parasites.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100557"},"PeriodicalIF":4.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000381/pdfft?md5=ee9ca1f5f6eea35ce2b8b29b0d76d4d1&pid=1-s2.0-S2211320724000381-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008764","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":"Erratum to “Uncovering the antimalarial potential of toad venoms through a bioassay-guided fractionation process” [Int. J. Parasitol.: Drugs Drug Resist. 20 (2022) 97–107]","authors":"","doi":"10.1016/j.ijpddr.2023.10.002","DOIUrl":"10.1016/j.ijpddr.2023.10.002","url":null,"abstract":"","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100510"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320723000325/pdfft?md5=0d8e8e74e09173394e44da7777759996&pid=1-s2.0-S2211320723000325-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41235103","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":"Quantitative tests of albendazole resistance in Caenorhabditis elegans beta-tubulin mutants","authors":"J.B. Collins ,&nbsp;Skyler A. Stone ,&nbsp;Emily J. Koury ,&nbsp;Anna G. Paredes ,&nbsp;Fiona Shao ,&nbsp;Crystal Lovato ,&nbsp;Michael Chen ,&nbsp;Richelle Shi ,&nbsp;Anwyn Y. Li ,&nbsp;Isa Candal ,&nbsp;Khadija Al Moutaa ,&nbsp;Nicolas D. Moya ,&nbsp;Erik C. Andersen","doi":"10.1016/j.ijpddr.2024.100556","DOIUrl":"10.1016/j.ijpddr.2024.100556","url":null,"abstract":"<div><p>Benzimidazole (BZ) anthelmintics are among the most important treatments for parasitic nematode infections in the developing world. Widespread BZ resistance in veterinary parasites and emerging resistance in human parasites raise major concerns for the continued use of BZs. Knowledge of the mechanisms of resistance is necessary to make informed treatment decisions and circumvent resistance. Benzimidazole resistance has traditionally been associated with mutations and natural variants in the <em>C. elegans</em> beta-tubulin gene <em>ben-1</em> and orthologs in parasitic species. However, variants in <em>ben-1</em> alone do not explain the differences in BZ responses across parasite populations. Here, we examined the roles of five <em>C. elegans</em> beta-tubulin genes (<em>tbb-1</em>, <em>mec-7</em>, <em>tbb-4</em>, <em>ben-1</em>, and <em>tbb-6</em>) in the BZ response as well as to determine if another beta-tubulin acts redundantly with <em>ben-1</em>. We generated <em>C. elegans</em> strains with a loss of each beta-tubulin gene, as well as strains with a loss of <em>tbb-1</em>, <em>mec-7</em>, <em>tbb-4</em>, or <em>tbb-6</em> in a genetic background that also lacks <em>ben-1</em>. We found that the loss of <em>ben-1</em> conferred the maximum level of resistance following exposure to a single concentration of albendazole, and the loss of a second beta-tubulin gene did not alter the level of resistance. However, additional traits other than larval development could be affected by the loss of additional beta-tubulins, and the roles of other beta-tubulin genes might be revealed at different albendazole concentrations. Therefore, further work is needed to fully define the possible roles of other beta-tubulin genes in the BZ response.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100556"},"PeriodicalIF":4.1,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221132072400037X/pdfft?md5=d41292adfb720dac255a79c591f51ed0&pid=1-s2.0-S221132072400037X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590255","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":"Phylogenetic and transcriptomic study of aldo-keto reductases in Haemonchus contortus and their inducibility by flubendazole","authors":"Karolína Štěrbová,&nbsp;Lucie Raisová Stuchlíková,&nbsp;Nikola Rychlá,&nbsp;Kateřina Kohoutová,&nbsp;Markéta Babičková,&nbsp;Lenka Skálová,&nbsp;Petra Matoušková","doi":"10.1016/j.ijpddr.2024.100555","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100555","url":null,"abstract":"<div><p>Aldo-keto reductases (AKRs), a superfamily of NADP(H)-dependent oxidoreductases, catalyze the oxidoreduction of a wide variety of eobiotic and xenobiotic aldehydes and ketones. In mammals, AKRs play essential roles in hormone and xenobiotic metabolism, oxidative stress, and drug resistance, but little is known about these enzymes in the parasitic nematode <em>Haemonchus contortus</em>. In the present study, 22 AKR genes existing in the <em>H. contortus</em> genome were investigated and a phylogenetic analysis with comparison to AKRs in <em>Caenorhabditis elegans</em>, sheep and humans was conducted. The constitutive transcription levels of all AKRs were measured in eggs, larvae, and adults of <em>H. contortus</em>, and their expression was compared in a drug-sensitive strain (ISE) and a benzimidazole-resistant strain (IRE) previously derived from the sensitive strain by imposing benzimidazole selection pressure. In addition, the inducibility of AKRs by exposure of <em>H. contortus</em> adults to benzimidazole anthelmintic flubendazole <em>in vitro</em> was tested. Phylogenetic analysis demonstrated that the majority of AKR genes in <em>H. contortus</em> lack orthologues in the sheep genome, which is a favorable finding for considering AKRs as potential drug targets. Large differences in the expression levels of individual AKRs were observed, with AKR1, AKR3, AKR8, and AKR10 being the most highly expressed at most developmental stages. Significant changes in the expression of AKRs during the life cycle and pronounced sex differences were found. Comparing the IRE and ISE strains, three AKRs were upregulated, and seven AKRs were downregulated in adults. In addition, the expression of three AKRs was induced by flubendazole exposure in adults of the ISE strain. Based on these results, AKR1, AKR2, AKR3, AKR5, AKR10 and AKR19 in particular merit further investigation and functional characterization with respect to their potential involvement in drug biotransformation and anthelmintic resistance in <em>H. contortus</em>.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100555"},"PeriodicalIF":4.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000368/pdfft?md5=c93325ee1e10575c2febe46eaf79a324&pid=1-s2.0-S2211320724000368-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141593798","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":"Effect of Phlebotomus papatasi on the fitness, infectivity and antimony-resistance phenotype of antimony-resistant Leishmania major Mon-25","authors":"Nalia Mekarnia ,&nbsp;Kamal-Eddine Benallal ,&nbsp;Jovana Sádlová ,&nbsp;Barbora Vojtková ,&nbsp;Aurélie Mauras ,&nbsp;Nicolas Imbert ,&nbsp;Maryline Longhitano ,&nbsp;Zoubir Harrat ,&nbsp;Petr Volf ,&nbsp;Philippe M. Loiseau ,&nbsp;Sandrine Cojean","doi":"10.1016/j.ijpddr.2024.100554","DOIUrl":"10.1016/j.ijpddr.2024.100554","url":null,"abstract":"<div><p><em>Leishmania major</em> is responsible for zoonotic cutaneous leishmaniasis. Therapy is mainly based on the use of antimony-based drugs; however, treatment failures and illness relapses were reported. Although studies were developed to understand mechanisms of drug resistance, the interactions of resistant parasites with their reservoir hosts and vectors remain poorly understood. Here we compared the development of two <em>L. major</em> MON-25 trivalent antimony-resistant lines, selected by a stepwise <em>in vitro</em> Sb(III)-drug pressure, to their wild-type parent line in the natural vector <em>Phlebotomus papatasi.</em> The intensity of infection, parasite location and morphological forms were compared by microscopy. Parasite growth curves and IC₅₀ values have been determined before and after the passage in <em>Ph. papatasi</em>. qPCR was used to assess the amplification rates of some antimony-resistance gene markers. In the digestive tract of sand flies, Sb(III)-resistant lines developed similar infection rates as the wild-type lines during the early-stage infections, but significant differences were observed during the late-stage of the infections. Thus, on day 7 p. i., resistant lines showed lower representation of heavy infections with colonization of the stomodeal valve and lower percentage of metacyclic promastigote forms in comparison to wild-type strains. Observed differences between both resistant lines suggest that the level of Sb(III)-resistance negatively correlates with the quality of the development in the vector. Nevertheless, both resistant lines developed mature infections with the presence of infective metacyclic forms in almost half of infected sandflies. The passage of parasites through the sand fly guts does not significantly influence their capacity to multiply <em>in vitro</em>. The IC₅₀ values and molecular analysis of antimony-resistance genes showed that the resistant phenotype of Sb(III)-resistant parasites is maintained after passage through the sand fly. Sb(III)-resistant lines of <em>L. major</em> MON-25 were able to produce mature infections in <em>Ph. papatasi</em> suggesting a possible circulation in the field using this vector.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100554"},"PeriodicalIF":4.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000356/pdfft?md5=3d804440cf8a4772d393c9ad582aca43&pid=1-s2.0-S2211320724000356-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467811","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":"In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii","authors":"Yanhua Qiu ,&nbsp;Bintao Zhai ,&nbsp;Yubin Bai ,&nbsp;Hongling Lin ,&nbsp;Lingyu Wu ,&nbsp;Wei Luo ,&nbsp;Mengyan Shi ,&nbsp;Shulin Chen ,&nbsp;Jiyu Zhang","doi":"10.1016/j.ijpddr.2024.100552","DOIUrl":"10.1016/j.ijpddr.2024.100552","url":null,"abstract":"<div><p><em>Toxoplasma gondii</em> (<em>T. gondii</em>) is a highly successful global parasite, infecting about one-third of the world's population and significantly affecting human life and the economy. However, current drugs for toxoplasmosis treatment have considerable side effects, and there is no specific drug to meet current needs. This study aims to evaluate the anti-<em>T. gondii</em> activity of broxaldine (BRO) <em>in vitro</em> and <em>in vivo</em> and explore its mechanism of action. Our results showed that compared to the control group, the invasion rate of tachyzoites in the 4 μg/mL BRO group was only 14.31%, and the proliferation rate of tachyzoites in host cells was only 1.23%. Furthermore, BRO disrupted the lytic cycle of <em>T. gondii</em> and reduced the size and number of cysts <em>in vitro</em>. A mouse model of acute toxoplasmosis reported a 41.5% survival rate after BRO treatment, with reduced parasite load in tissues and blood. The subcellular structure of <em>T. gondii</em> was observed, including disintegration of <em>T. gondii</em>, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in <em>T. gondii</em> treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-<em>T. gondii</em> activity <em>in vitro</em> and <em>in vivo</em>; therefore, it has the potential to be used as a lead compound for anti-<em>T. gondii</em> treatment.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100552"},"PeriodicalIF":4.1,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000332/pdfft?md5=ea67480b952bf320577dc0399ea13b71&pid=1-s2.0-S2211320724000332-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579582","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":"Efficacy of the bumped kinase inhibitor BKI-1708 against the cyst-forming apicomplexan parasites Toxoplasma gondii and Neospora caninum in vitro and in experimentally infected mice","authors":"Maria Cristina Ferreira de Sousa ,&nbsp;Dennis Imhof ,&nbsp;Kai Pascal Alexander Hänggeli ,&nbsp;Ryan Choi ,&nbsp;Matthew A. Hulverson ,&nbsp;Samuel L.M. Arnold ,&nbsp;Wesley C. Van Voorhis ,&nbsp;Erkang Fan ,&nbsp;Sánchez-Sánchez Roberto ,&nbsp;Luis M. Ortega-Mora ,&nbsp;Andrew Hemphill","doi":"10.1016/j.ijpddr.2024.100553","DOIUrl":"10.1016/j.ijpddr.2024.100553","url":null,"abstract":"<div><p><em>Toxoplasma gondii</em> and <em>Neospora caninum</em> are major worldwide morbidity-causing pathogens. Bumped kinase inhibitors (BKIs) are a compound class that has been optimized to target the apicomplexan calcium-dependent protein kinase 1 (CDPK1) – and several members of this class have proven to be safe and highly active <em>in vitro</em> and <em>in vivo</em>. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited <em>in vitro</em> IC₅₀ values of 120 nM for <em>T. gondii</em> and 480 nM for <em>N. caninum</em> β-galactosidase expressing strains, and did not affect human foreskin fibroblast (HFF) viability at concentrations up to 25 μM. Electron microscopy established that exposure of tachyzoite-infected fibroblasts to 2.5 μM BKI-1708 <em>in vitro</em> induced the formation of multinucleated schizont-like complexes (MNCs), characterized by continued nuclear division and harboring newly formed intracellular zoites that lack the outer plasma membrane. These zoites were unable to finalize cytokinesis to form infective tachyzoites. BKI-1708 did not affect zebrafish (<em>Danio rerio</em>) embryo development during the first 96 h following egg hatching at concentrations up to 2 μM. Treatments of mice with BKI-1708 at 20 mg/kg/day during five consecutive days resulted in drug plasma levels ranging from 0.14 to 4.95 μM. <em>In vivo</em> efficacy of BKI-1708 was evaluated by oral application of 20 mg/kg/day from day 9–13 of pregnancy in mice experimentally infected with <em>N. caninum</em> (NcSpain-7) tachyzoites or <em>T. gondii</em> (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100553"},"PeriodicalIF":4.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000344/pdfft?md5=05337ab18fdd00386b0462cc8f9ec858&pid=1-s2.0-S2211320724000344-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450433","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}