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

{"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}

{"title":"Lower micromolar activity of the antifungal imidazoles on the bacterial-type bifunctional aldehyde/alcohol dehydrogenase (AdhE) in Cryptosporidium parvum and in vitro efficacy against the zoonotic parasite","authors":"Haichuan Chen ,&nbsp;Dongqiang Wang ,&nbsp;Chenchen Wang ,&nbsp;Peng Jiang ,&nbsp;Mingxiao Liu ,&nbsp;Jigang Yin ,&nbsp;Yonglan Yu","doi":"10.1016/j.ijpddr.2024.100551","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100551","url":null,"abstract":"<div><p><em>Cryptosporidium parvum</em> is a waterborne and foodborne zoonotic protozoan parasite, a causative agent of moderate to severe diarrheal diseases in humans and animals. However, fully effective treatments are unavailable for medical and veterinary uses. There is a need to explore new drug targets for potential development of new therapeutics. Because <em>C. parvum</em> relies on anaerobic metabolism to produce ATP, fermentative enzymes in this parasite are attractive targets for exploration. In this study, we investigated the ethanol-fermentation in the parasite and characterized the basic biochemical features of a bacterial-type bifunctional aldehyde/alcohol dehydrogenase, namely CpAdhE. We also screened 3892 chemical entries from three libraries and identified 14 compounds showing &gt;50% inhibition on the enzyme activity of CpAdhE. Intriguingly, antifungal imidazoles and unsaturated fatty acids are the two major chemical groups among the top hits. We further characterized the inhibitory kinetics of selected imidazoles and unsaturated fatty acids on CpAdhE. These compounds displayed lower micromolar activities on CpAdhE (i.e., <em>IC</em>₅₀ values ranging from 0.88 to 11.02 μM for imidazoles and 8.93 to 35.33 μM for unsaturated fatty acids). Finally, we evaluated the in vitro anti-cryptosporidial efficacies and cytotoxicity of three imidazoles (i.e., tioconazole, miconazole and isoconazole). The three antifungal imidazoles exhibited lower micromolar efficacies against the growth of <em>C. parvum</em> in vitro (<em>EC</em>₅₀ values ranging from 4.85 to 10.41 μM and selectivity indices ranging from 5.19 to 10.95). The results provide a proof-of-concept data to support that imidazoles are worth being further investigated for potential development of anti-cryptosporidial therapeutics.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000320/pdfft?md5=a7fb67473afd2fb254b3759143180530&pid=1-s2.0-S2211320724000320-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141313418","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":"Ouabain, ATPase inhibitor, potentially enhances the effect of polyhexamethylene biguanide on Acanthamoeba castellanii","authors":"Kuang-Yi Shih ,&nbsp;Yao-Tsung Chang ,&nbsp;Yu-Jen Wang ,&nbsp;Jian-Ming Huang","doi":"10.1016/j.ijpddr.2024.100550","DOIUrl":"10.1016/j.ijpddr.2024.100550","url":null,"abstract":"<div><p><em>Acanthamoeba</em>, a free-living amoeba, is commonly found in various natural environments, such as rivers and soil, as well as in public baths, swimming pools, and sewers. <em>Acanthamoeba</em> can cause severe illness such as granulomatous amoebic encephalitis and Acanthamoeba keratitis (AK) in humans. AK, the most recognized disease, can cause permanent visual impairment or blindness by affecting the cornea. AK commonly affects contact lens wearers who neglect proper cleaning habits. The symptoms of AK include epithelial and stromal destruction, corneal infiltrate, and intense ocular pain, occasionally necessitating surgical removal of the entire eyeball. Current AK treatment involves the hourly application of eye drops containing polyhexamethylene biocide (PHMB). However, studies have revealed their ineffectiveness against drug-resistant strains. <em>Acanthamoeba</em> can form cysts as a survival mechanism in adverse environments, though the exact mechanism remains unknown. Our experiments revealed that sodium P-type ATPase (ACA1_065450) is closely linked to encystation. In addition, various encystation buffers, such as MgCl₂ or NaCl, induced the expression of P-type ATPase. Furthermore, we used ouabain, an ATPase inhibitor, to inhibit the Na⁺/K⁺ ion pump, consequently decreasing the encystation rate of <em>Acanthamoeba</em>. Our primary objective is to develop an advanced treatment for AK. We anticipate that the combination of ouabain and PHMB may serve as an effective therapeutic approach against AK in the future.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000319/pdfft?md5=8a2b658d161227b10a8f26e5fc564a5a&pid=1-s2.0-S2211320724000319-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141527","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":"First case of macrocyclic lactone-resistant Dirofilaria immitis in Europe - Cause for concern","authors":"Donato Traversa ,&nbsp;Anastasia Diakou ,&nbsp;Mariasole Colombo ,&nbsp;Sohini Kumar ,&nbsp;Thavy Long ,&nbsp;Serafeim C. Chaintoutis ,&nbsp;Luigi Venco ,&nbsp;Gianluca Betti Miller ,&nbsp;Roger Prichard","doi":"10.1016/j.ijpddr.2024.100549","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100549","url":null,"abstract":"<div><p>Heartworm disease caused by the nematode <em>Dirofilaria immitis</em> is one of the most important parasitoses of dogs. The treatment of the infection is long, complicated, risky and expensive. Conversely, prevention is easy, safe, and effective and it is achieved by the administration of macrocyclic lactones (MLs). In recent years, <em>D. immitis</em> strains resistant to MLs have been described in Southern USA, raising concerns for possible emergence, or spreading in other areas of the world. The present study describes the first case of ML-resistant <em>D. immitis</em> in a dog in Europe. The dog arrived in Rome, Italy, from USA in 2023. Less than 6 months after its arrival in Italy, the dog tested positive for <em>D. immitis</em> circulating antigen and microfilariae, despite it having received monthly the ML milbemycin oxime (plus an isoxazoline) after arrival. The microfilariae suppression test suggested a resistant strain. Microfilariae DNA was examined by droplet digital PCR-based duplex assays targeting four marker positions at single nucleotide polymorphisms (SNP1, SNP2, SNP3, SNP7) which differentiate resistant from susceptible isolates. The genetic analysis showed that microfilariae had a ML-resistant genotype at SNP1 and SNP7 positions, compatible with a resistant strain. It is unlikely that the dog acquired the infection after its arrival in Europe, while it is biologically and epidemiologically plausible that the dog was already infected when imported from USA to Europe. The present report highlights the realistic risk of ML-resistant <em>D. immitis</em> strains being imported and possibly transmitted in Europe and other areas of the world. Monitoring dogs travelling from one area to another, especially if they originate from regions where ML-resistance is well-documented, is imperative. Scientists, practitioners, and pet owners should be aware of the risk and remain vigilant against ML-resistance, in order to monitor and reduce the spreading of resistant <em>D. immitis</em>.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000307/pdfft?md5=3b7f04a849b1315ec7c73f8b0182faf0&pid=1-s2.0-S2211320724000307-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095643","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":"Repurposing DrugBank compounds as potential Plasmodium falciparum class 1a aminoacyl tRNA synthetase multi-stage pan-inhibitors with a specific focus on mitomycin","authors":"Fisayo Olotu ,&nbsp;Mariscal Brice Tchatat Tali ,&nbsp;Curtis Chepsiror ,&nbsp;Olivier Sheik Amamuddy ,&nbsp;Fabrice Fekam Boyom ,&nbsp;Özlem Tastan Bishop","doi":"10.1016/j.ijpddr.2024.100548","DOIUrl":"10.1016/j.ijpddr.2024.100548","url":null,"abstract":"<div><p><em>Plasmodium falciparum</em> aminoacyl tRNA synthetases (PfaaRSs) are potent antimalarial targets essential for proteome fidelity and overall parasite survival in every stage of the parasite's life cycle. So far, some of these proteins have been singly targeted yielding inhibitor compounds that have been limited by incidences of resistance which can be overcome via pan-inhibition strategies. Hence, herein, for the first time, we report the identification and <em>in vitro</em> antiplasmodial validation of <strong>Mitomycin</strong> (<strong>MMC</strong>) as a probable pan-inhibitor of class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis. We combined multiple <em>in silico</em> structure-based discovery strategies that first helped identify functional and druggable sites that were preferentially targeted by the compound in each of the plasmodial proteins: Ins1-Ins2 domain in Pf-ARS; anticodon binding domain in Pf-CRS; CP1-editing domain in Pf-IRS and Pf-MRS; C-terminal domain in Pf-LRS; and CP-core region in Pf-VRS. Molecular dynamics studies further revealed that <strong>MMC</strong> allosterically induced changes in the global structures of each protein. Likewise, prominent structural perturbations were caused by the compound across the functional domains of the proteins. More so, <strong>MMC</strong> induced systematic alterations in the binding of the catalytic nucleotide and amino acid substrates which culminated in the loss of key interactions with key active site residues and ultimate reduction in the nucleotide-binding affinities across all proteins, as deduced from the binding energy calculations. These altogether confirmed that <strong>MMC</strong> uniformly disrupted the structure of the target proteins and essential substrates. Further, <strong>MMC</strong> demonstrated <em>IC</em>_<em>50</em> &lt; 5 μM against the Dd2 and 3D7 strains of parasite making it a good starting point for malarial drug development. We believe that findings from our study will be important in the current search for highly effective multi-stage antimalarial drugs.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000290/pdfft?md5=6251aac0cd410b41f7cb2265f47c4b80&pid=1-s2.0-S2211320724000290-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141134026","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":"Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box","authors":"Javier Chao-Pellicer ,&nbsp;Iñigo Arberas-Jiménez ,&nbsp;Ines Sifaoui ,&nbsp;José E. Piñero ,&nbsp;Jacob Lorenzo-Morales","doi":"10.1016/j.ijpddr.2024.100545","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100545","url":null,"abstract":"<div><p><em>Naegleria fowleri</em>, known as the brain-eating amoeba, is the pathogen that causes the primary amoebic meningoencephalitis (PAM), a severe neurodegenerative disease with a fatality rate exceeding 95%. Moreover, PAM cases commonly involved previous activities in warm freshwater bodies that allow amoebae-containing water through the nasal passages. Hence, awareness among healthcare professionals and the general public are the key to contribute to a higher and faster number of diagnoses worldwide. Current treatment options for PAM, such as amphotericin B and miltefosine, are limited by potential cytotoxic effects. In this context, the repurposing of existing compounds has emerged as a promising strategy. In this study, the evaluation of the COVID Box which contains 160 compounds demonstrated significant in vitro amoebicidal activity against two type strains of <em>N. fowleri</em>. From these compounds, terconazole, clemastine, ABT-239 and PD-144418 showed a higher selectivity against the parasite compared to the remaining products. In addition, programmed cell death assays were conducted with these four compounds, unveiling compatible metabolic events in treated amoebae. These compounds exhibited chromatin condensation and alterations in cell membrane permeability, indicating their potential to induce programmed cell death. Assessment of mitochondrial membrane potential disruption and a significant reduction in ATP production emphasized the impact of these compounds on the mitochondria, with the identification of increased ROS production underscoring their potential as effective treatment options. This study emphasizes the potential of the mentioned COVID Box compounds against <em>N. fowleri</em>, providing a path for enhanced PAM therapies.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000265/pdfft?md5=349c6ecff988102637e77e002263689b&pid=1-s2.0-S2211320724000265-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140878606","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":"Acaricide resistance status of livestock ticks from East and West Africa and in vivo efficacy of acaricides to control them","authors":"Alec Evans ,&nbsp;Maxime Madder ,&nbsp;Josephus Fourie ,&nbsp;Lénaïg Halos ,&nbsp;Bersissa Kumsa ,&nbsp;Elikira Kimbita ,&nbsp;Joseph Byaruhanga ,&nbsp;Frank Norbert Mwiine ,&nbsp;Dennis Muhanguzi ,&nbsp;Safiou Bienvenu Adehan ,&nbsp;Alassane Toure ,&nbsp;Jahashi Nzalawahe ,&nbsp;Fred Aboagye-Antwi ,&nbsp;Ndudim Isaac Ogo ,&nbsp;Leon Meyer ,&nbsp;Frans Jongejan ,&nbsp;Imad Bouzaidi Cheikhi ,&nbsp;Maggie Fisher ,&nbsp;Peter Holdsworth","doi":"10.1016/j.ijpddr.2024.100541","DOIUrl":"10.1016/j.ijpddr.2024.100541","url":null,"abstract":"<div><p>Through a collaborative effort across six Sub-Saharan African countries, using recognized international assessment techniques, 23 stocks of three tick species (<em>Rhipicephalus microplus, Rhipicephalus appendiculatus</em> and <em>Amblyomma variegatum)</em> of economic importance for rural small holder farming communities from East and West Africa were collected from cattle<em>,</em> and evaluated in <em>in vitro</em> larval packet tests (LPT). The results demonstrated medium to high resistance to chlorfenvinphos and amitraz across species. <em>Rhipicephalus microplus</em> demonstrated high level alpha-cypermethrin and cypermethrin resistance. Stocks of <em>A</em>. <em>variegatum</em> (West Africa) and <em>R</em>. <em>appendiculatus</em> (Uganda) demonstrated medium level ivermectin resistance.</p><p>The four least susceptible stocks (East and West African <em>R. microplus, A. variegatum</em> and <em>R. appendiculatus)</em> were taken into <em>in vivo</em> controlled cattle studies where fipronil was found effective against West and East African <em>R. microplus</em> isolates although persistent efficacy failed to reach 90%. Cymiazole and cypermethrin, and ivermectin based acaricides were partially effective against <em>R. microplus</em> without persistent efficacy. Flumethrin spray-on killed <em>A. variegatum</em> within 72 h for up to 10 days posttreatment, however product application was directly to tick attachment sites, which may be impractical under field conditions. A flumethrin pour-on formulation on goats provided persistent efficacy against <em>A. variegatum</em> for up to one-month. Therapeutic control was achieved against <em>R. appendiculatus</em> through weekly spraying cattle with flumethrin, amitraz or combined cymiazole and cypermethrin. A fipronil pour-on product offered four-week residual control against <em>R. appendiculatus</em> (with slow onset of action).</p><p>Few studies have assessed and directly compared acaricidal activity <em>in vitro</em> and <em>in vivo.</em> There was some discordance between efficacy indicated by LPT and <em>in vivo</em> results. This observation calls for more research into accurate and affordable assessment methods for acaricide resistance.</p><p>No single active or product was effective against all three tick species, emphasising the need for the development of alternative integrated tick management solutions.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000228/pdfft?md5=bda4ea540bd633855a1234e58b6eac46&pid=1-s2.0-S2211320724000228-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957300","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}