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

{"title":"In vitro and in vivo activities of a trithiolato-diRuthenium complex conjugated with sulfadoxine against the apicomplexan parasite Toxoplasma gondii","authors":"Ghalia Boubaker ,&nbsp;Alice Bernal ,&nbsp;Anitha Vigneswaran ,&nbsp;Dennis Imhof ,&nbsp;Maria Cristina Ferreira de Sousa ,&nbsp;Kai Pascal Alexander Hänggeli ,&nbsp;Noé Haudenschild ,&nbsp;Julien Furrer ,&nbsp;Emilia Păunescu ,&nbsp;Oksana Desiatkina ,&nbsp;Andrew Hemphill","doi":"10.1016/j.ijpddr.2024.100544","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100544","url":null,"abstract":"<div><p>Organometallic compounds, including Ruthenium complexes, have been widely developed as anti-cancer chemotherapeutics, but have also attracted much interest as potential anti-parasitic drugs. Recently hybrid drugs composed of organometallic Ruthenium moieties that were complexed to different antimicrobial agents were synthesized. One of these compounds, a trithiolato-diRuthenium complex (RU) conjugated to sulfadoxine (SDX), inhibited proliferation of <em>Toxoplasma gondii</em> tachyzoites grown in human foreskin fibroblast (HFF) monolayers with an IC₅₀ &lt; 150 nM, while SDX and the non-modified RU complex applied either individually or as an equimolar mixture were much less potent. In addition, conjugation of SDX to RU lead to decreased HFF cytotoxicity. RU-SDX did not impair the <em>in vitro</em> proliferation of murine splenocytes at concentrations ranging from 0.1 to 0.5 μM but had an impact at 2 μM, and induced zebrafish embryotoxicity at 20 μM, but not at 2 or 0.2 μM. RU-SDX acted parasitostatic but not parasiticidal, and induced transient ultrastructural changes in the mitochondrial matrix of tachyzoites early during treatment. While other compounds that target the mitochondrion such as the uncouplers FCCP and CCCP and another trithiolato-Ruthenium complex conjugated to adenine affected the mitochondrial membrane potential, no such effect was detected for RU-SDX. Evaluation of the <em>in vivo</em> efficacy of RU-SDX in a murine <em>T. gondii</em> oocyst infection model comprised of non-pregnant outbred CD1 mice showed no effects on the cerebral parasite burden, but reduced parasite load in the eyes and in heart tissue.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100544"},"PeriodicalIF":4.0,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000253/pdfft?md5=1758646700d4ce7a5e7b5857d8207d26&pid=1-s2.0-S2211320724000253-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140825399","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":"Plasmodium RNA triphosphatase validation as antimalarial target","authors":"Sonia Moliner-Cubel ,&nbsp;Noemi Bahamontes-Rosa ,&nbsp;Ane Rodriguez-Alejandre ,&nbsp;Pamela M. Nassau ,&nbsp;Argyrides Argyrou ,&nbsp;Anshu Bhardwaja ,&nbsp;Rachel C. Buxton ,&nbsp;David Calvo-Vicente ,&nbsp;Bernadette Mouzon ,&nbsp;William McDowell ,&nbsp;Alfonso Mendoza-Losana ,&nbsp;Maria G. Gomez-Lorenzo","doi":"10.1016/j.ijpddr.2024.100537","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100537","url":null,"abstract":"<div><p>Target-based approaches have traditionally been used in the search for new anti-infective molecules. Target selection process, a critical step in Drug Discovery, identifies targets that are essential to establish or maintain the infection, tractable to be susceptible for inhibition, selective towards their human ortholog and amenable for large scale purification and high throughput screening. The work presented herein validates the <em>Plasmodium falciparum</em> mRNA 5’ triphosphatase (PfPRT1), the first enzymatic step to cap parasite nuclear mRNAs, as a candidate target for the development of new antimalarial compounds. mRNA capping is essential to maintain the integrity and stability of the messengers, allowing their translation. PfPRT1 has been identified as a member of the tunnel, metal dependent mRNA 5′ triphosphatase family which differs structurally and mechanistically from human metal independent mRNA 5′ triphosphatase. In the present study the essentiality of PfPRT1 was confirmed and molecular biology tools and methods for target purification, enzymatic assessment and target engagement were developed, with the goal of running a future high throughput screening to discover PfPRT1 inhibitors.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100537"},"PeriodicalIF":4.0,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000186/pdfft?md5=e5fae98317910cf914e2a408c67afefe&pid=1-s2.0-S2211320724000186-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141163643","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":"Nourseothricin as a novel drug for selection of transgenic Giardia lamblia","authors":"Corina D. Wirdnam ,&nbsp;Dawid Warmus ,&nbsp;Carmen Faso","doi":"10.1016/j.ijpddr.2024.100543","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100543","url":null,"abstract":"<div><p>Functional gene and protein characterizations in parasitic protists are often limited by their genetic tractability. Despite the development of CRISPR-Cas9-derived or inspired approaches for a handful of protist parasites, the overall genetic tractability of these organisms remains limited. The intestinal parasite <em>Giardia lamblia</em> is one such species, with the added challenge of a paucity of reliable selection markers.</p><p>To address this limitation, we tested the feasibility of using Nourseothricin as an effective selection agent in Giardia. Here, we report that axenically-grown WB <em>Giardia</em> cells are sensitive to Nourseothricin and that engineering expression of the streptothricin acetyltransferase (SAT-1) gene from <em>Streptomyces rochei</em> in transgenic parasites confers resistance to this antibiotic. Furthermore, we determine that SAT-1-expressing parasites are cross-resistant neither to Neomycin nor Puromycin, which are widely used to select for transgenic parasites. Consequently, we show that Nourseothricin can be used in sequential combination with both Neomycin and Puromycin to select for dual transfection events.</p><p>This work increases the number of reliable selection agents and markers for <em>Giardia</em> genetic manipulation, expanding the limited molecular toolbox for this species of global medical importance.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100543"},"PeriodicalIF":4.0,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000241/pdfft?md5=a08affe1983c77d439da5cd975827679&pid=1-s2.0-S2211320724000241-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140807091","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":"Treating cryptosporidiosis: A review on drug discovery strategies","authors":"Anne-Charlotte Lenière,&nbsp;Alexis Vlandas,&nbsp;Jérôme Follet","doi":"10.1016/j.ijpddr.2024.100542","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100542","url":null,"abstract":"<div><p>Despite several decades of research on therapeutics, cryptosporidiosis remains a major concern for human and animal health. Even though this field of research to assess antiparasitic drug activity is highly active and competitive, only one molecule is authorized to be used in humans. However, this molecule was not efficacious in immunocompromised people and the lack of animal therapeutics remains a cause of concern. Indeed, the therapeutic arsenal needs to be developed for both humans and animals. Our work aims to clarify research strategies that historically were diffuse and poorly directed. This paper reviews <em>in vitro</em> and <em>in vivo</em> methodologies to assess the activity of future therapeutic compounds by screening drug libraries or through drug repurposing. It focuses on High Throughput Screening methodologies (HTS) and discusses the lack of knowledge of target mechanisms. In addition, an overview of several specific metabolic pathways and enzymatic activities used as targets against <em>Cryptosporidium</em> is provided. These metabolic processes include glycolytic pathways, fatty acid production, kinase activities, tRNA elaboration, nucleotide synthesis, gene expression and mRNA maturation. As a conclusion, we highlight emerging future strategies for screening natural compounds and assessing drug resistance issues.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100542"},"PeriodicalIF":4.0,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221132072400023X/pdfft?md5=2c999fcac43efe99f255fbf85f5d4e5d&pid=1-s2.0-S221132072400023X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140645476","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":"Evaluation of the antiplasmodial efficacy of synthetic 2,5-diphenyloxazole analogs of compounds naturally derived from Oxytropis lanata","authors":"Nanang R. Ariefta ,&nbsp;Koichi Narita ,&nbsp;Toshihiro Murata ,&nbsp;Yoshifumi Nishikawa","doi":"10.1016/j.ijpddr.2024.100540","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100540","url":null,"abstract":"<div><p>The persistent prevalence and dissemination of drug-resistant malaria parasites continue to challenge the progress of malaria eradication efforts. As a result, there is an urgent need to search for and develop innovative therapies. In this study, we screened synthetic 2,5-diphenyloxazole analogs from <em>Oxytropis lanata</em>. Among 48 compounds, 14 potently inhibited the proliferation of <em>P. falciparum</em> strains 3D7 (chloroquine-sensitive) and K1 (multidrug-resistant) in vitro, exhibited IC₅₀ values from 3.38 to 12.65 μM and 1.27–6.19 μM, respectively, and were toxic to human foreskin fibroblasts at 39.53–336.35 μM. Notably, Compounds <strong>31</strong> (2-(2′,3′-dimethoxyphenyl)-5-(2″-hydroxyphenyl)oxazole) and <strong>32</strong> (2-(2′,3′-dimethoxyphenyl)-5-(2″-benzyloxyphenyl)oxazole) exhibited the highest selectivity indices (SIs) against both <em>P. falciparum</em> strains (3D7/K1), with values &gt; 40.20/&gt;126.58 and &gt; 41.27/&gt; 59.06, respectively. In the IC₅₀ speed and stage-specific assays, Compounds <strong>31</strong> and <strong>32</strong> showed slow action, along with distinct effects on the ring and trophozoite stages. Microscopy observations further revealed that both compounds impact the development and delay the progression of the trophozoite and schizont stages in <em>P. falciparum</em> 3D7, especially at concentrations 100 times their IC₅₀ values. In a 72-h in vitro exposure experiment at their respective IC₈₀ in <em>P. falciparum</em> 3D7, significant alterations in parasitemia levels were observed compared to the untreated group. In Compound <strong>31</strong>-treated cultures, parasites shrank and were unable to reinvade red blood cells (RBCs) during an extended 144-h incubation period, even after compound removal from the culture. In vivo assessments were conducted on <em>P. yoelii</em> 17XNL-infected mice treated with Compounds <strong>31</strong> and <strong>32</strong> at 20 mg/kg administered once daily for ten days. The treated groups showed statistically significant lower peaks of parasitemia (Compound <strong>31</strong>-treated: trial 1 12.7%, trial 2 15.8%; Compound <strong>32</strong>-treated: trial 1 12.7%, trial 2 14.0%) compared to the untreated group (trial 1 21.7%, trial 2 28.3%). These results emphasize the potential of further developing 2,5-diphenyloxazoles as promising antimalarial agents.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100540"},"PeriodicalIF":4.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000216/pdfft?md5=1dfb0cb947387ac4f75ca834b9284ec5&pid=1-s2.0-S2211320724000216-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140650693","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":"High-throughput prioritization of target proteins for development of new antileishmanial compounds","authors":"Lucas G. Azevedo ,&nbsp;Ezequiel Sosa ,&nbsp;Artur T.L. de Queiroz ,&nbsp;Aldina Barral ,&nbsp;Richard J. Wheeler ,&nbsp;Marisa F. Nicolás ,&nbsp;Leonardo P. Farias ,&nbsp;Dario Fernández Do Porto ,&nbsp;Pablo Ivan P. Ramos","doi":"10.1016/j.ijpddr.2024.100538","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100538","url":null,"abstract":"<div><p>Leishmaniasis, a vector-borne disease, is caused by the infection of <em>Leishmania</em> spp., obligate intracellular protozoan parasites. Presently, human vaccines are unavailable, and the primary treatment relies heavily on systemic drugs, often presenting with suboptimal formulations and substantial toxicity, making new drugs a high priority for LMIC countries burdened by the disease, but a low priority in the agenda of most pharmaceutical companies due to unattractive profit margins. New ways to accelerate the discovery of new, or the repositioning of existing drugs, are needed. To address this challenge, our study aimed to identify potential protein targets shared among clinically-relevant <em>Leishmania</em> species. We employed a subtractive proteomics and comparative genomics approach, integrating high-throughput multi-omics data to classify these targets based on different druggability metrics. This effort resulted in the ranking of 6502 ortholog groups of protein targets across 14 pathogenic <em>Leishmania</em> species. Among the top 20 highly ranked groups, metabolic processes known to be attractive drug targets, including the ubiquitination pathway, aminoacyl-tRNA synthetases, and purine synthesis, were rediscovered. Additionally, we unveiled novel promising targets such as the nicotinate phosphoribosyltransferase enzyme and dihydrolipoamide succinyltransferases. These groups exhibited appealing druggability features, including less than 40% sequence identity to the human host proteome, predicted essentiality, structural classification as highly druggable or druggable, and expression levels above the 50th percentile in the amastigote form. The resources presented in this work also represent a comprehensive collection of integrated data regarding trypanosomatid biology.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100538"},"PeriodicalIF":4.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000198/pdfft?md5=fb65abd832eb2668709c9d19b5045eda&pid=1-s2.0-S2211320724000198-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140644215","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":"Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria","authors":"Zhuoru Jin ,&nbsp;Wei Pang ,&nbsp;Yan Zhao ,&nbsp;Hui Min ,&nbsp;Shijie Yao ,&nbsp;Zhifang Bian ,&nbsp;Yixin Wen ,&nbsp;Chuanyang Peng ,&nbsp;Yaming Cao ,&nbsp;Li Zheng","doi":"10.1016/j.ijpddr.2024.100539","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100539","url":null,"abstract":"<div><p>Infection with <em>Plasmodium falciparum</em> is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, <em>Plasmodium berghei</em> ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100539"},"PeriodicalIF":4.0,"publicationDate":"2024-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000204/pdfft?md5=01acea5ceacbc6298fc27269173191f8&pid=1-s2.0-S2211320724000204-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140551028","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":"Discovery of antiplasmodial pyridine carboxamides and thiocarboxamides","authors":"Alexa Redway ,&nbsp;Christina Spry ,&nbsp;Ainka Brown ,&nbsp;Ursula Wiedemann ,&nbsp;Imam Fathoni ,&nbsp;Larnelle F. Garnie ,&nbsp;Deyun Qiu ,&nbsp;Timothy J. Egan ,&nbsp;Adele M. Lehane ,&nbsp;Yvette Jackson ,&nbsp;Kevin J. Saliba ,&nbsp;Nadale Downer-Riley","doi":"10.1016/j.ijpddr.2024.100536","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100536","url":null,"abstract":"<div><p>Malaria continues to be a significant burden, particularly in Africa, which accounts for 95% of malaria deaths worldwide. Despite advances in malaria treatments, malaria eradication is hampered by insecticide and antimalarial drug resistance. Consequently, the need to discover new antimalarial lead compounds remains urgent. To help address this need, we evaluated the antiplasmodial activity of twenty-two amides and thioamides with pyridine cores and their non-pyridine analogues. Twelve of these compounds showed <em>in vitro</em> anti-proliferative activity against the intraerythrocytic stage of <em>Plasmodium falciparum</em>, the most virulent species of <em>Plasmodium</em> infecting humans. Thiopicolinamide <strong>13i</strong> was found to possess submicromolar activity (IC₅₀ = 142 nM) and was &gt;88-fold less active against a human cell line. The compound was equally effective against chloroquine-sensitive and -resistant parasites and did not inhibit β-hematin formation, pH regulation or <em>Pf</em>ATP4. Compound <strong>13i</strong> may therefore possess a novel mechanism of action.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100536"},"PeriodicalIF":4.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000174/pdfft?md5=764fef1dfcf7fb9e855badc572300146&pid=1-s2.0-S2211320724000174-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140644250","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":"Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies","authors":"Marzuq A. Ungogo ,&nbsp;Harry P. de Koning","doi":"10.1016/j.ijpddr.2024.100533","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100533","url":null,"abstract":"<div><p>Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus <em>Trypanosoma</em>, and the main species infecting domesticated animals are <em>T. brucei brucei</em>, <em>T. b. rhodesiense</em>, <em>T. congolense</em>, <em>T. simiae</em>, <em>T. vivax</em>, <em>T. evansi</em> and <em>T. equiperdum</em>. AT transmission, again depending on species, is through tsetse flies or common <em>Stomoxys</em> and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"25 ","pages":"Article 100533"},"PeriodicalIF":4.0,"publicationDate":"2024-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000149/pdfft?md5=bfe511b8f01007efd11880ee75b2289f&pid=1-s2.0-S2211320724000149-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140330652","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":"Absence of association between Pfnfs1 mutation and in vitro susceptibility to lumefantrine in Plasmodium falciparum","authors":"Weilin Zeng ,&nbsp;Wei Zhao ,&nbsp;Hao Wei ,&nbsp;Yucheng Qin ,&nbsp;Zheng Xiang ,&nbsp;Yanrui Wu ,&nbsp;Xi Chen ,&nbsp;Yanmei Zhang ,&nbsp;Hui Zhao ,&nbsp;Mengxi Duan ,&nbsp;Wenya Zhu ,&nbsp;Kemin Sun ,&nbsp;Yiman Wu ,&nbsp;Tao Liang ,&nbsp;Ye Mou ,&nbsp;Cheng Liu ,&nbsp;Xiuya Tang ,&nbsp;Yaming Huang ,&nbsp;Liwang Cui ,&nbsp;Zhaoqing Yang","doi":"10.1016/j.ijpddr.2024.100532","DOIUrl":"https://doi.org/10.1016/j.ijpddr.2024.100532","url":null,"abstract":"<div><p>Artemether-lumefantrine (AL) is the most widely used antimalarial drug for treating uncomplicated falciparum malaria. This study evaluated whether the K65Q mutation in the <em>Plasmodium falciparum</em> cysteine desulfurase IscS (<em>Pfnfs1</em>) gene was associated with alternated susceptibility to lumefantrine using clinical parasite samples from Ghana and the China-Myanmar border area. Parasite isolates from the China-Myanmar border had significantly higher IC₅₀ values to lumefantrine than parasites from Ghana. In addition, the K65 allele was significantly more prevalent in the Ghanaian parasites (34.5%) than in the China-Myanmar border samples (6.8%). However, no difference was observed in the lumefantrine IC₅₀ value between the <em>Pfnfs1</em> reference K65 allele and the non reference 65Q allele in parasites from the two regions. These data suggest that the <em>Pfnfs1</em> K65Q mutation may not be a reliable marker for reduced susceptibility to lumefantrine.</p></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"24 ","pages":"Article 100532"},"PeriodicalIF":4.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2211320724000137/pdfft?md5=88e8ba3e526c6d464307769bdaacd141&pid=1-s2.0-S2211320724000137-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140187387","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}