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

{"title":"Licochalcone a: A promising antiparasitic drug against giardiasis","authors":"Yingying Zhang ,&nbsp;Wenchao Zhao ,&nbsp;Haili Du ,&nbsp;Pitambar Dhakal ,&nbsp;Xinyi Chen ,&nbsp;Longfei Wu ,&nbsp;Xiaoying Li ,&nbsp;Rongjun Wang ,&nbsp;Longxian Zhang ,&nbsp;Sumei Zhang ,&nbsp;Junqiang Li","doi":"10.1016/j.ijpddr.2024.100573","DOIUrl":"10.1016/j.ijpddr.2024.100573","url":null,"abstract":"<div><div>Giardiasis, caused by <em>Giardia duodenalis</em>, is a prevalent and significant zoonotic disease. While nitroimidazole drugs are primarily used to treat giardiasis, the urgent need for the development and formulation of new drugs has arisen due to increasing drug resistance. Several plant derived medicine have been employed as antiparasitic drugs. This study has evaluated the anti-<em>Giardia</em> effect of Licochalcone A (Lic A) through both <em>in vitro</em> and <em>in vivo</em> experiments. We determined the 50% inhibitory concentration (IC₅₀) of Lic A, analyzed the adhesive ability of <em>G. duodenalis</em>, and assessed intestinal morphology and various indicators in the gerbil model. The <em>in vitro</em> assays demonstrated that the IC₅₀ value of Lic A against <em>G. duodenalis</em> was 27.42 μM. Additionally, Lic A significantly inhibited the adhesiveability of <em>G. duodenalis</em> trophozoites, impairing their cell structure and cytoskeleton. <em>In vivo</em> experiments showed that Lic A significantly mitigated weight loss due to <em>G. duodenalis</em> infection, and lowered the intestinal parasite load. Histopathological examinations in gerbils indicated that Lic A could reduce intestinal damage, increase the height of intestinal villi, decrease crypt depth, and maintain the integrity of intestinal structure. Furthermore, Lic A altered cytokine levels and enhanced the body's antioxidant capacity. In conclusion, Lic A exbibits significant anti-<em>Giardia</em> effects both <em>in vitro</em> and <em>in vivo</em>, suggesting its potential as a promising antiparasitic drug candidate against giardiasis.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100573"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854037","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":"Investigation of the threonine metabolism of Echinococcus multilocularis: The threonine dehydrogenase as a potential drug target in alveolar echinococcosis","authors":"Marc Kaethner ,&nbsp;Pascal Zumstein ,&nbsp;Joachim Müller ,&nbsp;Matías Preza ,&nbsp;Philipp Grossenbacher ,&nbsp;Anissa Bartetzko ,&nbsp;Laura Vetter ,&nbsp;Martin Lochner ,&nbsp;Stefan Schürch ,&nbsp;Clement Regnault ,&nbsp;Daniel Villalobos Ramírez ,&nbsp;Britta Lundström-Stadelmann","doi":"10.1016/j.ijpddr.2025.100581","DOIUrl":"10.1016/j.ijpddr.2025.100581","url":null,"abstract":"<div><div>Alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of the fox tapeworm <em>Echinococcus multilocularis</em>. We recently showed that <em>E. multilocularis</em> metacestode vesicles scavenge large amounts of L-threonine from the culture medium. This motivated us to study the effect of L-threonine on the parasite and how it is metabolized. We established a novel metacestode vesicle growth assay with an automated readout, which showed that L-threonine treatment led to significantly increased parasite growth. In addition, L-threonine increased the formation of novel metacestode vesicles from primary parasite cell cultures in contrast to the non-proteinogenic threonine analog 3-hydroxynorvaline. Tracing of [U-¹³C]-L-threonine and metabolites in metacestode vesicles and culture medium resulted in the detection of [U-¹³C]-labeling in aminoacetone and glycine, indicating that L-threonine was metabolized by threonine dehydrogenase (TDH). EmTDH-mediated threonine metabolism in the <em>E. multilocularis</em> metacestode stage was further confirmed by quantitative real-time PCR, which demonstrated high expression of <em>emtdh</em> in <em>in vitro</em> cultured metacestode vesicles and also in metacestode samples obtained from infected animals. EmTDH was enzymatically active in metacestode vesicle extracts. The compounds disulfiram, myricetin, quercetin, sanguinarine, and seven quinazoline carboxamides were evaluated for their ability to inhibit recombinantly expressed EmTDH. The most potent inhibitors, albeit not very strong or highly specific, were disulfiram, myricetin and sanguinarine. These compounds were subsequently tested for activity against <em>E. multilocularis</em> metacestode vesicles and primary parasite cells and only sanguinarine demonstrated significant <em>in vitro</em> activity. However, TDH is not its only cellular target, and it is also known to be highly toxic. Our findings suggest that additional targets of sanguinarine should be explored, and that it may serve as a foundation for developing more specific compounds against the parasite. Moreover, the EmTDH assay could be a valuable high-throughput, target-based platform for discovering novel anti-echinococcal compounds.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100581"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028707","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":"Modified dosing schedule efficacy of fosmidomycin and clindamycin against murine malaria Plasmodium berghei","authors":"Leah A. Walker,&nbsp;Vision Bagonza,&nbsp;Bryce Bobb,&nbsp;David J. Sullivan","doi":"10.1016/j.ijpddr.2024.100577","DOIUrl":"10.1016/j.ijpddr.2024.100577","url":null,"abstract":"<div><div>Fosmidomycin and clindamycin target the <em>Plasmodium</em> apicoplast. Combination clinical trials have produced mixed results with the primary problem being the recrudescent infection frequency by day 28. Given that antibiotic efficacy against bacterial infections often depends on the constant drug presence over several days, we hypothesized that the antimalarial blood or liver stage efficacy of fosmidomycin and clindamycin could be improved by implementing a more frequent dosing schedule. A blood stage murine malaria <em>P. berghei</em> GFP-luciferase low and high parasitemia model was implemented to follow pharmacodynamics and cure for modified dose, schedule and duration of individual and combination fosmidomycin and clindamycin. <em>P. berghei</em> sporozoites were used to investigate fosmidomycin during the 48 h murine liver stage. Here we observed that the same total dose of fosmidomycin and clindamycin, alone and in combination, are more efficacious when scheduled in smaller, more frequent doses. Fosmidomycin added measurably small additional killing in combination with clindamycin. Despite dosing every 6 h during liver stages, fosmidomycin was inhibitory, but noncurative even with addition of atorvastatin to decrease hepatocyte production of mevalonate. We have also demonstrated <em>in vitro</em> efficacy of fosmidomycin and clindamycin against <em>P. falciparum</em> C580Y with IC₅₀s similar to those for drug sensitive <em>P. falciparum</em>. The dosing schedule of quinoline and artemisinin partner drugs fosmidomycin or clindamycin targeting the apicoplast should maximize time above minimum inhibitory concentration.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100577"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921657","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":"Nitroxoline evidence amoebicidal activity against Acanthamoeba castellanii through DNA damage and the stress response pathways","authors":"Lijun Chen ,&nbsp;Wei Han ,&nbsp;Wenwen Jing ,&nbsp;Meng Feng ,&nbsp;Qingtong Zhou ,&nbsp;Xunjia Cheng","doi":"10.1016/j.ijpddr.2025.100578","DOIUrl":"10.1016/j.ijpddr.2025.100578","url":null,"abstract":"<div><div><em>Acanthamoeba castellanii</em> is a widespread unicellular eukaryote found in diverse environments, including tap water, soil, and swimming pools. It is responsible for severe infections, such as <em>Acanthamoeba</em> keratitis and granulomatous amebic encephalitis, particularly in individuals with immunocompromisation. The ability of protozoans to form dormant and persistent cysts complicates treatment, as current therapies are ineffective against cyst stages and suffer from poor specificity and side effects. Nitroxoline, a quinoline derivative with well-established antibacterial, antifungal, and antiviral properties, is a promising therapeutic candidate. This study aimed to elucidate cellular signalling events that counteract the effects of nitroxoline. In this study, nitroxoline significantly reduced the viability of <em>A</em>. <em>castellanii</em> trophozoites in a dose- and time-dependent manner, inducing morphological changes and apoptosis. Transcriptomic analysis revealed substantial alterations in gene expression, including enrichment of metabolic pathways, DNA damage responses, and iron ion binding. Nitroxoline treatment upregulated genes involved in DNA repair and oxidative stress response while regulating genes in the methionine and cysteine cycles. It also decreased the mitochondrial membrane potential, H₂S production, and total iron amount in <em>A</em>. <em>castellanii</em>. Bioinformatic analyses and molecular docking studies suggest direct interactions between nitroxoline and several <em>A</em>. <em>castellanii</em> proteins. Our research provides a comprehensive molecular map of the response of <em>A</em>. <em>castellanii</em> to nitroxoline, revealing significant changes in gene expression related to the stress response and metabolic pathways. These findings underscore the potential of nitroxoline as a potent anti-<em>Acanthamoeba</em> agent, offering new insights into its mechanism of action and paving the way for effective combinational therapeutic strategies.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100578"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052439","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":"Investigation of risk factors associated with Ancylostoma spp. infection and the benzimidazole F167Y resistance marker polymorphism in dogs from the United States","authors":"Pablo D. Jimenez Castro ,&nbsp;Jennifer L. Willcox ,&nbsp;Haresh Rochani ,&nbsp;Holly L. Richmond ,&nbsp;Heather E. Martinez ,&nbsp;Cecilia E. Lozoya ,&nbsp;Christian Savard ,&nbsp;Christian M. Leutenegger","doi":"10.1016/j.ijpddr.2025.100584","DOIUrl":"10.1016/j.ijpddr.2025.100584","url":null,"abstract":"<div><div><em>Ancylostoma caninum</em> is the most significant intestinal nematode parasite of dogs. We acquired fecal surveillance data from a large population of dogs in the United States (US). A diagnostic test using real-time PCR (qPCR) for <em>Ancylostoma</em> spp. and allele-specific qPCR detecting the SNP F167Y in the isotype 1 of the Beta-tubulin gene, was used in 885,424 randomized canine fecal samples collected between March 2022 and December 2023. Overall, <em>Ancylostoma</em> spp. had a prevalence of 1.76% (15,537/885,424), with the highest in the South 3.73% (10,747/287,576), and the lowest in the West 0.45% (632/140,282). Within the subset of <em>Ancylostoma</em> spp<em>.-</em>detected dogs used for further analysis, the F167Y SNP had an overall prevalence of 14.44% with the highest in the West and the lowest in the Midwest (10.76%). The greyhound exhibited a higher prevalence of <em>Ancylostoma</em> spp. infections (17.03%) and a higher prevalence of the F167Y polymorphism (33.6%) compared to non-greyhounds (13.7% and 2.08%), respectively, but were not associated with the highest risk for the F167Y polymorphism. Sex did not influence hookworm infection nor F167Y polymorphism prevalence. Intact dogs had a prevalence of hookworm infection and F167Y polymorphism of 3.88% and 15.66%, respectively. Puppies showed increased prevalence of hookworms (3.70%) and the F167Y SNP (17.1%). Greyhounds, bluetick coonhounds, and boerboels had the highest relative risks for hookworm infection, while Cavalier King Charles spaniels, Havanese, and shiba inus had the lowest. The top and bottom three with the highest and lowest RR for the F167Y SNP were the old English sheepdog, American foxhound, and toy poodle Toy, and shih tzu, Maltese, and Australian cattle dogs, respectively. This study highlights the value of an accessible diagnostic qPCR test with fast turnaround in unraveling the molecular epidemiology of hookworms and benzimidazole resistance, as well as explore potentially important risk factorsin dogs with routine veterinary care.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100584"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143222955","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 faecal egg count reduction test: Will identification of larvae to species improve its utility?","authors":"Dave Leathwick,&nbsp;Peter Green,&nbsp;Charlotte Bouchet,&nbsp;Alex Chambers,&nbsp;Tania Waghorn,&nbsp;Christian Sauermann","doi":"10.1016/j.ijpddr.2025.100589","DOIUrl":"10.1016/j.ijpddr.2025.100589","url":null,"abstract":"<div><div>In the faecal egg count reduction test, visual identification of larvae cultured from faeces enables the egg counts to be apportioned to species/genera, resulting in a more accurate test. However, morphology cannot reliably differentiate some species meaning that, in some cases, efficacy can only be estimated at the genus or species-complex level. We investigated the benefits of identifying larvae to species using DNA to determine how often this would alter the diagnosis of resistance and whether increasing the number of larvae identified would alter the repeatability of an efficacy estimate.</div><div>Data on faecal nematode egg counts and the corresponding larval species mixes were acquired from tests conducted on commercial sheep farms. The proportion of each species present in faecal culture was determined using DNA. Efficacy was then compared for individual species and for those genera/species complexes which cannot reliably be differentiated visually. The proportion of each species present was subsequently resampled 10,000 times (repeated random sampling) and efficacy recalculated to produce the median efficacy, along with the 5 % and 95 % simulation percentiles. Subsequently, the number of larvae sampled to determine the species mix in each sample was varied from 50 to 6400 and the process repeated.</div><div>Of 152 comparisons of efficacy, 25 % of cases where genus-level identification resulted in a finding of ‘susceptible’ for that category, species-level identification returned at least one diagnosis of ‘resistant’ i.e., genus-level identification resulted in a 25 % false negative diagnosis.</div><div>When the number of larvae sampled for species identification was low (&lt;400) variation in efficacy estimates was high, however, as sample size increased the confidence interval around the efficacy estimate decreased.</div><div>The results indicate that identifying large numbers of larvae to species using DNA has the potential to increase the accuracy and confidence in efficacy estimates achieved using the faecal egg count reduction test.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100589"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726167","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":"Culturing of Giardia lamblia under microaerobic conditions can impact metronidazole susceptibility by inducing increased expression of antioxidant enzymes","authors":"Kateryna Starynets ,&nbsp;Ana Paunkov ,&nbsp;Anja Wagner ,&nbsp;Klaus Kratochwill ,&nbsp;Christian Klotz ,&nbsp;David Leitsch","doi":"10.1016/j.ijpddr.2025.100585","DOIUrl":"10.1016/j.ijpddr.2025.100585","url":null,"abstract":"<div><div>The microaerophilic/anaerobic protist <em>Giardia lamblia</em> is a world-wide occurring parasite of the human small intestine. It causes giardiasis which manifests as diarrhoea accompanied by other sequelae. Giardiasis is most commonly treated with either the 5-nitroimidazole metronidazole or the benzimidazole albendazole. Unfortunately, the number of refractory cases is increasing, which is probably caused, at least in part, by drug resistance. However, most attempts to isolate metronidazole-resistant <em>G</em>. <em>lamblia</em> strains from patients have failed so far because the parasites were not resistant when tested <em>in vitro</em>.</div><div>We hypothesized that this failure might be caused by drug assay conditions which are standardly anaerobic, and performed metronidazole susceptibility testing with two well studied strains, i.e. WB C6 and BRIS/87/HEPU/713 (strain 713) under microaerophilic conditions. Indeed, 713 proved to be less susceptible to metronidazole under microaerophilic conditions as compared to anaerobic conditions, and residual growth was even noted at concentrations of metronidazole similar to those in the serum of treated patients (i.e. about 100 μM). Further experiments showed that 713 also grows much faster under microaerobic conditions than WB C6. Reduced susceptibility to metronidazole under microaerobic conditions was also observed in a clinical isolate from a refractory giardiasis case.</div><div>Two-dimensional gel electrophoresis showed that microaerobic growth was accompanied by the upregulation of superoxide reductase, a pyridoxamine 5′-phosphate oxidase putative domain-containing protein, and a TlpA-like protein in 713 but not in WB C6. All three proteins are known, or can be predicted to have antioxidant functions. Indeed, overexpression of pyridoxamine 5′-phosphate oxidase in WB C6 from a plasmid carrying the respective gene behind the arginine deiminase promoter significantly improved growth of the transfected cell line under microaerobic conditions. Moreover, similarly overexpressed superoxide reductase conferred significant protection against metronidazole.</div><div>Our results suggest that oxygen concentrations can affect the outcomes of metronidazole treatment against <em>G</em>. <em>lamblia</em>.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100585"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143179624","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":"Recent in vitro advances in the ocular antimicrobial agents against Acanthamoeba","authors":"Chun-Hsien Chen ,&nbsp;Jian-Ming Huang ,&nbsp;Yu-Jen Wang ,&nbsp;Chih-Ming Tsai ,&nbsp;Wei-Chen Lin","doi":"10.1016/j.ijpddr.2025.100586","DOIUrl":"10.1016/j.ijpddr.2025.100586","url":null,"abstract":"<div><div>This review examines the advancements in antimicrobial drug discovery with in vitro assays for <em>Acanthamoeba</em>, highlighting the efficacy of current topical antimicrobial agents. In recent decades, the treatment and diagnosis of Acanthamoeba keratitis (AK) have presented clinical challenges. Clinicians often rely on clinical judgment, risk factors, and patient travel history to guide initial treatment decisions. The clinical presentation of AK frequently coincides with bacterial and fungal keratitis, leading to delays in diagnostic confirmation. This review compiles a list of commonly used antimicrobial agents that may be useful in controlling and preventing <em>Acanthamoeba</em> and other microbial infections during the diagnostic waiting period. Due to their unique life cycle, consisting of both trophozoite and cyst stages, amoebae exhibit resistance to various clinical drugs. Current research efforts are focused on identifying alternative and effective treatment options. Despite the ongoing characterization of various cytocidal agents from natural and synthetic sources, chlorhexidine gluconate (CHG) and polyhexamethylene biguanide (PHMB) have emerged as the most effective therapies for AK. Drawing from previous studies, we catalog several commonly used antimicrobial agents that may enhance the efficacy of PHMB and CHG while also preventing other microbial infections. These alternative agents present promising options for treating AK cases. This review evaluates progress in anti-amoebic drug discovery, focusing on antibiotics and cataloging their activity at different stages of <em>Acanthamoeba</em>.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100586"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562765","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 binuclear cyclopalladated complex CP2 is targeting ubiquinol-cytochrome c reductase (complex III) of Leishmania amazonensis","authors":"Angela Maria Arenas Velásquez ,&nbsp;Irwin Alexander Patino Linares ,&nbsp;Lawrence D. Gaspers ,&nbsp;Paula J. Bartlett ,&nbsp;Jecika M. Velasques ,&nbsp;Adelino V.G. Netto ,&nbsp;Andrew P. Thomas ,&nbsp;Marcia A.S. Graminha","doi":"10.1016/j.ijpddr.2024.100574","DOIUrl":"10.1016/j.ijpddr.2024.100574","url":null,"abstract":"<div><div>Leishmaniasis is a neglected disease that remains with a limited number of drugs available for chemotherapy and has an increased drug resistance that affects treatment outcomes. Metal-based drugs such as cyclopalladated complex [Pd(dmba)(μ-N₃)]₂ (<strong>CP2</strong>), a <em>Leishmania</em> topoisomerase IB inhibitor involved in calcium dysregulation and mitochondrial dysfunction of the parasite, had been an alternative to outline the appearance of chemoresistance. To identify new molecular targets and point out possible resistance mechanisms, a <strong>CP2</strong>-resistant <em>Leishmania amazonensis</em> (<em>LaR</em>) was selected by stepwise exposure to increasing drug pressure until a line capable of growth in 13.3 μM <strong>CP2</strong>. <em>LaR</em> IC₅₀ value was 52.4 μM (4-fold higher than <em>L. amazonensis</em>–wild type, <em>La</em>). <em>LaR</em> promastigotes were cross-resistant to other DNA topoisomerase I inhibitors (camptothecin) and more susceptible to anti-leishmanial drugs pentamidine and miltefosine. A protective effect on cell viability was observed by pretreating the parasite with Ca²⁺ channel blockers followed by <strong>CP2</strong> in <em>La</em> but not in <em>LaR</em>. Analyses of the cell viability of <em>La</em> and <em>LaR</em> using electron transport chain (ETC) inhibitors demonstrated that <em>La</em> is more sensitive than <em>LaR</em>. The studies of mitochondrial oxygen consumption demonstrated that <em>LaR</em> is less susceptible to complex III (ubiquinol-cytochrome <em>c</em> reductase – CcR) inhibitor, antimycin A (AA). CcR activities of <em>La</em> and <em>LaR</em> were equal for both strains in the absence of <strong>CP2</strong> and significantly decreased, 69 % for <em>La</em> and 51 % for <em>LaR</em>, in the presence of <strong>CP2</strong>. This resistance is attributed to overexpression of CcR, confirmed by the RT-qPCR. CcR inhibition by <strong>CP2</strong> leads the parasite to increase the reactive oxygen species (ROS) production, principally in <em>La.</em> Therefore, in this work, we suggested that CcR is the main target of <strong>CP2</strong> in the mitochondria, acting to inhibit mitochondria respiratory, and the <em>LaR</em> mutant has increased activity of CcR, which reduces the formation of ROS.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100574"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921659","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 graphical user interface for wrmXpress 2.0 streamlines helminth phenotypic screening","authors":"Zachary Caterer ,&nbsp;Rachel V. Horejsi ,&nbsp;Carly Weber ,&nbsp;Blake Mathisen ,&nbsp;Chase N. Nelson ,&nbsp;Maggie Bagatta ,&nbsp;Ireland Coughlin ,&nbsp;Megan Wettstein ,&nbsp;Ankit Kulshrestha ,&nbsp;Hui Siang Benjamin Lee ,&nbsp;Leonardo R. Nunn ,&nbsp;Mostafa Zamanian ,&nbsp;Nicolas J. Wheeler","doi":"10.1016/j.ijpddr.2025.100588","DOIUrl":"10.1016/j.ijpddr.2025.100588","url":null,"abstract":"<div><div>Image-based phenotypic screening is a fundamental technique used to better understand the basic biology of helminths and advance discovery of new anthelmintics. Miniaturization of screening platforms and automated microscopy have led to a surge in imaging data and necessitated software to organize and analyze these data. Traditionally, these analyses are performed remotely on high-performance computers, often requiring an understanding of a command line interface (CLI) and the ability to write scripts to control the software or job scheduler. Requiring access to specialized computing equipment and advanced computational skills raises the barrier to entry for these sorts of studies. The development of efficient, performant computer and graphical processing units for personal computers and cheaper imaging solutions has made the requirement of remote servers superfluous for many small to medium-scale screens, but most analytical software still require interaction with a CLI. To democratize the analysis of image-based phenotypic screens, we have developed a graphical user interface (GUI) for wrmXpress, a tool that integrates many popular computational pipelines for analyzing imaging data of parasitic and free-living worms. The GUI operates on any personal computer using the operating system's native web browser, allowing users to configure and run analyses using a point-and-click approach. Containerization of the application eliminates the need to install specialized programming libraries and dependencies, further increasing the ease of use. GUI development required a substantial reorganization of the wrmXpress backend codebase, which allowed for the addition of a new pipeline for high-resolution tracking of worm behavior, and we demonstrate its functionality by showing that praziquantel modulates the behavior of <em>Schistosoma mansoni</em> miracidia. These advances make cutting-edge analyses of image-based phenotyping of worms more equitable and accessible.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"Article 100588"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143678955","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}