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

{"title":"In artemisinin-resistant falciparum malaria parasites, mitochondrial metabolic pathways are essential for survival but not those of apicoplast","authors":"","doi":"10.1016/j.ijpddr.2024.100565","DOIUrl":"10.1016/j.ijpddr.2024.100565","url":null,"abstract":"<div><div>Emergence and spread of parasite resistance to artemisinins, the first-line antimalarial therapy, threaten the malaria eradication policy. To identify therapeutic targets to eliminate artemisinin-resistant parasites, the functioning of the apicoplast and the mitochondrion was studied, focusing on the fatty acid synthesis type II (FASII) pathway in the apicoplast and the electron transfer chain in the mitochondrion. A significant enrichment of the FASII pathway among the up-regulated genes in artemisinin-resistant parasites under dihydroartemisinin treatment was found, in agreement with published transcriptomic data. However, using GC-MS analyzes of fatty acids, we demonstrated for the first time that the FASII pathway is non-functional, ruling out the use of FASII inhibitors to target artemisinin-resistant parasites. Conversely, by assessing the modulation of the oxygen consumption rate, we evidenced that mitochondrial respiration remains functional and flexible in artemisinin-resistant parasites and even at the quiescent stage. Two novel compounds targeting electron transport chain (ELQ300, ELQ400) efficiently killed quiescent artemisinin-resistant parasites. Therefore, mitochondrial respiration represents a key target for the elimination of artemisinin-resistant persistent <em>Plasmodium falciparum</em> parasites.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322497","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":"Evaluating the amoeba thioredoxin reductase selenoprotein as potential drug target for treatment of Acanthamoeba infections","authors":"","doi":"10.1016/j.ijpddr.2024.100564","DOIUrl":"10.1016/j.ijpddr.2024.100564","url":null,"abstract":"<div><div>The genus <em>Acanthamoeba</em> comprises facultative pathogens, causing <em>Acanthamoeba</em> keratitis (AK) and granulomatous amoebic encephalitis (GAE). In both diseases, treatment options are limited, and drug development is challenging. This study aimed to investigate the role of the large thioredoxin reductase selenoprotein of <em>Acanthamoeba</em> (AcTrxR-L) as a potential drug target assessing the effects of the thioredoxin reductase inhibitors auranofin, TRi-1, and TRi-2 on AcTrxR-L activity and on the viability of <em>Acanthamoeba</em> trophozoites. Recombinant expression and purification of AcTrxR-L as a selenoprotein allowed assessments of its enzymatic activity, with reduction of various substrates, including different thioredoxin isoforms. Auranofin demonstrated potent inhibition towards AcTrxR-L, followed by TRi-1, and TRi-2 exhibiting lower effectiveness. The inhibitors showed variable activity against trophozoites in culture, with TRi-1 and TRi-2 resulting in strongly impaired trophozoite viability. Cytotoxicity tests with human corneal epithelial cells revealed lower susceptibility to all compounds compared to <em>Acanthamoeba</em> trophozoites, underscoring their potential as future amoebicidal agents. Altogether, this study highlights the druggability of AcTrxR-L and suggests it to be a promising drug target for the treatment of <em>Acanthamoeba</em> infections. Further research is warranted to elucidate the role of AcTrxR-L in <em>Acanthamoeba</em> pathogenesis and to develop effective therapeutic strategies targeting this redox enzyme.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319637","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":"The phosphatase inhibitor BVT-948 can be used to efficiently screen functional sexual development proteins in the malaria parasite Plasmodium berghei","authors":"","doi":"10.1016/j.ijpddr.2024.100563","DOIUrl":"10.1016/j.ijpddr.2024.100563","url":null,"abstract":"<div><h3>Background</h3><p>Studying and discovering the molecular mechanism of <em>Plasmodium</em> sexual development is crucial for the development of transmission blocking drugs and malaria eradication. The aim of this study was to investigate the feasibility of using phosphatase inhibitors as a tool for screening proteins essential for <em>Plasmodium</em> sexual development and to discover proteins affecting the sexual development of malaria parasites.</p></div><div><h3>Methods</h3><p>Differences in protein phosphorylation among <em>Plasmodium</em> gametocytes incubated with BVT-948 under <em>in vitro</em> ookinete culture conditions were evaluated using phosphoproteomic methods. Gene Ontology (GO) analysis was performed to predict the mechanism by which BVT-948 affected gametocyte–ookinete conversion. The functions of 8 putative proteins involved in <em>Plasmodium berghei</em> sexual development were evaluated. Bioinformatic analysis was used to evaluate the possible mechanism of PBANKA_0100800 in gametogenesis and subsequent sexual development.</p></div><div><h3>Results</h3><p>The phosphorylation levels of 265 proteins decreased while those of 67 increased after treatment with BVT-948. Seven of the 8 genes selected for phenotype screening play roles in <em>P. berghei</em> sexual development, and 4 of these were associated with gametocytogenesis. PBANKA_0100800 plays essential roles in gametocyte–ookinete conversion and transmission to mosquitoes.</p></div><div><h3>Conclusions</h3><p>Seven proteins identified by screening affect <em>P. berghei</em> sexual development, suggesting that phosphatase inhibitors can be used for functional protein screening.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000447/pdfft?md5=9f49542e884503e417896ae68e574d58&pid=1-s2.0-S2211320724000447-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995707","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":"Inhibition of Giardia duodenalis by isocryptolepine -triazole adducts and derivatives","authors":"","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":null,"pages":null},"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":"Corrigendum to \"Efficacy of flukicides against Fasciola hepatica and first report of triclabendazole resistance on German sheep farms\" [Int. J. Parasitol. Drugs Drug Resist. 23 (2023) 94-105].","authors":"Alexandra Kahl, Georg von Samson-Himmelstjerna, Christina Helm, Jane Hodgkinson, Diana Williams, Wiebke Weiher, Werner Terhalle, Stephan Steuber, Martin Ganter, Jürgen Krücken","doi":"10.1016/j.ijpddr.2024.100562","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100562","url":null,"abstract":"","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017334","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":"Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products","authors":"","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":null,"pages":null},"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":"","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":null,"pages":null},"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":"","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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}