Pub Date : 2024-08-01DOI: 10.1016/j.ijpddr.2023.10.002
{"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}
Pub Date : 2024-07-09DOI: 10.1016/j.ijpddr.2024.100556
J.B. Collins , Skyler A. Stone , Emily J. Koury , Anna G. Paredes , Fiona Shao , Crystal Lovato , Michael Chen , Richelle Shi , Anwyn Y. Li , Isa Candal , Khadija Al Moutaa , Nicolas D. Moya , Erik C. Andersen
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 C. elegans beta-tubulin gene ben-1 and orthologs in parasitic species. However, variants in ben-1 alone do not explain the differences in BZ responses across parasite populations. Here, we examined the roles of five C. elegans beta-tubulin genes (tbb-1, mec-7, tbb-4, ben-1, and tbb-6) in the BZ response as well as to determine if another beta-tubulin acts redundantly with ben-1. We generated C. elegans strains with a loss of each beta-tubulin gene, as well as strains with a loss of tbb-1, mec-7, tbb-4, or tbb-6 in a genetic background that also lacks ben-1. We found that the loss of ben-1 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.
{"title":"Quantitative tests of albendazole resistance in Caenorhabditis elegans beta-tubulin mutants","authors":"J.B. Collins , Skyler A. Stone , Emily J. Koury , Anna G. Paredes , Fiona Shao , Crystal Lovato , Michael Chen , Richelle Shi , Anwyn Y. Li , Isa Candal , Khadija Al Moutaa , Nicolas D. Moya , 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}
Pub Date : 2024-07-08DOI: 10.1016/j.ijpddr.2024.100555
Karolína Štěrbová, Lucie Raisová Stuchlíková, Nikola Rychlá, Kateřina Kohoutová, Markéta Babičková, Lenka Skálová, Petra Matoušková
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 Haemonchus contortus. In the present study, 22 AKR genes existing in the H. contortus genome were investigated and a phylogenetic analysis with comparison to AKRs in Caenorhabditis elegans, sheep and humans was conducted. The constitutive transcription levels of all AKRs were measured in eggs, larvae, and adults of H. contortus, 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 H. contortus adults to benzimidazole anthelmintic flubendazole in vitro was tested. Phylogenetic analysis demonstrated that the majority of AKR genes in H. contortus 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 H. contortus.
{"title":"Phylogenetic and transcriptomic study of aldo-keto reductases in Haemonchus contortus and their inducibility by flubendazole","authors":"Karolína Štěrbová, Lucie Raisová Stuchlíková, Nikola Rychlá, Kateřina Kohoutová, Markéta Babičková, Lenka Skálová, 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}
Pub Date : 2024-06-24DOI: 10.1016/j.ijpddr.2024.100554
Nalia Mekarnia , Kamal-Eddine Benallal , Jovana Sádlová , Barbora Vojtková , Aurélie Mauras , Nicolas Imbert , Maryline Longhitano , Zoubir Harrat , Petr Volf , Philippe M. Loiseau , Sandrine Cojean
Leishmania major 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 L. major MON-25 trivalent antimony-resistant lines, selected by a stepwise in vitro Sb(III)-drug pressure, to their wild-type parent line in the natural vector Phlebotomus papatasi. 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 Ph. papatasi. 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 in vitro. 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 L. major MON-25 were able to produce mature infections in Ph. papatasi suggesting a possible circulation in the field using this vector.
大利什曼原虫是人畜共患皮肤利什曼病的罪魁祸首。治疗主要以使用锑基药物为主,但也有治疗失败和疾病复发的报道。虽然研究人员已经了解了抗药性的机制,但对抗药性寄生虫与其贮存宿主和载体之间的相互作用仍然知之甚少。在这里,我们比较了通过逐步体外Sb(III)-药物压力筛选出的两个L. major MON-25三价抗锑品系与其野生型亲本品系在自然载体Phlebotomus papatasi中的发展情况。通过显微镜比较了感染强度、寄生虫位置和形态。利用 qPCR 评估了一些抗锑基因标记的扩增率。在沙蝇的消化道中,Sb(III)抗性品系在感染初期的感染率与野生型品系相似,但在感染后期则出现了显著差异。因此,与野生型品系相比,抗性品系在第 7 天时表现出较低的重度感染率,并在气孔瓣膜上形成定殖,而中生原虫的比例也较低。两个抗性品系之间的差异表明,Sb(III)抗性水平与载体的发育质量呈负相关。尽管如此,两个抗性品系都发展出了成熟的感染,几乎一半的受感染沙蝇都出现了有感染力的元簇。寄生虫通过沙蝇内脏并不会对其体外繁殖能力产生重大影响。IC50 值和抗锑基因的分子分析表明,耐 Sb(III)寄生虫的抗锑表型在通过沙蝇后仍能保持。对 Sb(III)有抗性的 L. major MON-25 株系能够在 Ph. papatasi 中产生成熟的感染,这表明该病媒可能在田间流通。
{"title":"Effect of Phlebotomus papatasi on the fitness, infectivity and antimony-resistance phenotype of antimony-resistant Leishmania major Mon-25","authors":"Nalia Mekarnia , Kamal-Eddine Benallal , Jovana Sádlová , Barbora Vojtková , Aurélie Mauras , Nicolas Imbert , Maryline Longhitano , Zoubir Harrat , Petr Volf , Philippe M. Loiseau , 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 IC<sub>50</sub> 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 IC<sub>50</sub> 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}
Pub Date : 2024-06-20DOI: 10.1016/j.ijpddr.2024.100552
Yanhua Qiu , Bintao Zhai , Yubin Bai , Hongling Lin , Lingyu Wu , Wei Luo , Mengyan Shi , Shulin Chen , Jiyu Zhang
Toxoplasma gondii (T. gondii) 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-T. gondii activity of broxaldine (BRO) in vitro and in vivo 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 T. gondii and reduced the size and number of cysts in vitro. 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 T. gondii was observed, including disintegration of T. gondii, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in T. gondii treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-T. gondii activity in vitro and in vivo; therefore, it has the potential to be used as a lead compound for anti-T. gondii treatment.
{"title":"In vitro and in vivo activity evaluation and mode of action of broxaldine on Toxoplasma gondii","authors":"Yanhua Qiu , Bintao Zhai , Yubin Bai , Hongling Lin , Lingyu Wu , Wei Luo , Mengyan Shi , Shulin Chen , 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}
Pub Date : 2024-06-19DOI: 10.1016/j.ijpddr.2024.100553
Maria Cristina Ferreira de Sousa , Dennis Imhof , Kai Pascal Alexander Hänggeli , Ryan Choi , Matthew A. Hulverson , Samuel L.M. Arnold , Wesley C. Van Voorhis , Erkang Fan , Sánchez-Sánchez Roberto , Luis M. Ortega-Mora , Andrew Hemphill
Toxoplasma gondii and Neospora caninum 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 in vitro and in vivo. BKI-1708 is based on a 5-aminopyrazole-4-carboxamide scaffold, and exhibited in vitro IC50 values of 120 nM for T. gondii and 480 nM for N. caninum 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 in vitro 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 (Danio rerio) 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. In vivo 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 N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. This resulted in significantly decreased cerebral parasite loads and reduced vertical transmission in both models without drug-induced pregnancy interference.
{"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 , Dennis Imhof , Kai Pascal Alexander Hänggeli , Ryan Choi , Matthew A. Hulverson , Samuel L.M. Arnold , Wesley C. Van Voorhis , Erkang Fan , Sánchez-Sánchez Roberto , Luis M. Ortega-Mora , 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> IC<sub>50</sub> 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}
Pub Date : 2024-06-06DOI: 10.1016/j.ijpddr.2024.100551
Haichuan Chen , Dongqiang Wang , Chenchen Wang , Peng Jiang , Mingxiao Liu , Jigang Yin , Yonglan Yu
Cryptosporidium parvum 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 C. parvum 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 >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., IC50 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 C. parvum in vitro (EC50 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.
{"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 , Dongqiang Wang , Chenchen Wang , Peng Jiang , Mingxiao Liu , Jigang Yin , 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 >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><sub>50</sub> 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><sub>50</sub> 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":"25 ","pages":"Article 100551"},"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}
Acanthamoeba, 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. Acanthamoeba 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. Acanthamoeba 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 Acanthamoeba. 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.
棘阿米巴是一种自由生活的阿米巴,常见于各种自然环境中,如河流和土壤,以及公共浴池、游泳池和下水道。阿米巴原虫可导致严重疾病,如肉芽肿阿米巴脑炎和阿米巴角膜炎(AK)。AK是最常见的疾病,可通过影响角膜导致永久性视力损伤或失明。AK 通常会影响那些忽视正确清洁习惯的隐形眼镜佩戴者。AK 的症状包括角膜上皮和基质破坏、角膜浸润和剧烈眼痛,有时需要通过手术切除整个眼球。目前治疗 AK 的方法是每小时滴用含有聚六亚甲基生物杀灭剂(PHMB)的眼药水。但研究表明,这些药物对耐药菌株无效。棘阿米巴可以形成囊肿,作为在恶劣环境中的一种生存机制,但其确切机制尚不清楚。我们的实验发现,钠 P 型 ATP 酶(ACA1_065450)与囊肿的形成密切相关。此外,MgCl2或NaCl等各种气滞缓冲液都能诱导P型ATP酶的表达。此外,我们还使用了一种 ATPase 抑制剂--乌巴因(ouabain)来抑制 Na+/K+ 离子泵,从而降低了棘阿米巴的包囊率。我们的主要目标是开发一种先进的 AK 治疗方法。我们预计,uabain 和 PHMB 的组合将来可能会成为治疗 AK 的有效方法。
{"title":"Ouabain, ATPase inhibitor, potentially enhances the effect of polyhexamethylene biguanide on Acanthamoeba castellanii","authors":"Kuang-Yi Shih , Yao-Tsung Chang , Yu-Jen Wang , 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 MgCl<sub>2</sub> or NaCl, induced the expression of P-type ATPase. Furthermore, we used ouabain, an ATPase inhibitor, to inhibit the Na<sup>+</sup>/K<sup>+</sup> 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":"25 ","pages":"Article 100550"},"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}
Pub Date : 2024-05-21DOI: 10.1016/j.ijpddr.2024.100549
Donato Traversa , Anastasia Diakou , Mariasole Colombo , Sohini Kumar , Thavy Long , Serafeim C. Chaintoutis , Luigi Venco , Gianluca Betti Miller , Roger Prichard
Heartworm disease caused by the nematode Dirofilaria immitis 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, D. immitis 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 D. immitis 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 D. immitis 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 D. immitis 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 D. immitis.
由盘尾丝虫病线虫引起的心丝虫病是狗最重要的寄生虫病之一。该病的治疗过程漫长、复杂、风险高且费用昂贵。相反,通过服用大环内酯(ML)来预防则简单、安全、有效。近年来,美国南部出现了对大环内酯类药物有抗药性的白喉杆菌菌株,这引起了人们对白喉杆菌可能在世界其他地区出现或传播的担忧。本研究描述了欧洲首例对 ML 具有抗药性的白喉杆菌病例。这只狗于 2023 年从美国抵达意大利罗马。抵达意大利不到 6 个月后,尽管该犬在抵达后每月接受一次 ML 米尔贝霉素肟(外加一种异噁唑啉)治疗,但该犬的 D. immitis 循环抗原和微丝蚴检测结果呈阳性。微丝蚴抑制试验表明这是一种耐药菌株。微丝蚴 DNA 检测采用基于液滴数字 PCR 的双链检测法,针对单核苷酸多态性(SNP1、SNP2、SNP3 和 SNP7)的四个标记位点进行检测,这些标记位点可区分抗性和易感分离株。基因分析表明,微丝蚴在 SNP1 和 SNP7 位点上具有抗 ML 基因型,与抗性菌株相符。该犬不可能是在抵达欧洲后才感染的,而从生物学和流行病学角度来看,该犬从美国进口到欧洲时就已经感染了。本报告强调了耐甲型肝炎病毒株被输入并可能在欧洲和世界其他地区传播的现实风险。必须对从一个地区前往另一个地区的狗进行监控,尤其是当这些狗来自有充分证据表明对 ML 具有抗药性的地区时。科学家、从业人员和宠物主人都应意识到这一风险,并对耐甲流病毒保持警惕,以监测和减少耐甲流病毒的传播。
{"title":"First case of macrocyclic lactone-resistant Dirofilaria immitis in Europe - Cause for concern","authors":"Donato Traversa , Anastasia Diakou , Mariasole Colombo , Sohini Kumar , Thavy Long , Serafeim C. Chaintoutis , Luigi Venco , Gianluca Betti Miller , 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":"25 ","pages":"Article 100549"},"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}
Plasmodium falciparum 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 in vitro antiplasmodial validation of Mitomycin (MMC) 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 in silico 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 MMC 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, MMC 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 MMC uniformly disrupted the structure of the target proteins and essential substrates. Further, MMC demonstrated IC50 < 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.
{"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 , Mariscal Brice Tchatat Tali , Curtis Chepsiror , Olivier Sheik Amamuddy , Fabrice Fekam Boyom , 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><sub><em>50</em></sub> < 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":"25 ","pages":"Article 100548"},"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}