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

{"title":"Licochalcone a: A promising antiparasitic drug against giardiasis.","authors":"Yingying Zhang, Wenchao Zhao, Haili Du, Pitambar Dhakal, Xinyi Chen, Longfei Wu, Xiaoying Li, Rongjun Wang, Longxian Zhang, Sumei Zhang, Junqiang Li","doi":"10.1016/j.ijpddr.2024.100573","DOIUrl":"10.1016/j.ijpddr.2024.100573","url":null,"abstract":"<p><p>Giardiasis, caused by Giardia duodenalis, is a prevalent and significant zoonotic disease. While nitroimidazole drugs are primarily used to treat giardiasis, the urgent need for the development and formulation of new drugs has arisen due to increasing drug resistance. Several plant derived medicine have been employed as antiparasitic drugs. This study has evaluated the anti-Giardia effect of Licochalcone A (Lic A) through both in vitro and in vivo experiments. We determined the 50% inhibitory concentration (IC₅₀) of Lic A, analyzed the adhesive ability of G. duodenalis, and assessed intestinal morphology and various indicators in the gerbil model. The in vitro assays demonstrated that the IC₅₀ value of Lic A against G. duodenalis was 27.42 μM. Additionally, Lic A significantly inhibited the adhesiveability of G. duodenalis trophozoites, impairing their cell structure and cytoskeleton. In vivo experiments showed that Lic A significantly mitigated weight loss due to G. duodenalis infection, and lowered the intestinal parasite load. Histopathological examinations in gerbils indicated that Lic A could reduce intestinal damage, increase the height of intestinal villi, decrease crypt depth, and maintain the integrity of intestinal structure. Furthermore, Lic A altered cytokine levels and enhanced the body's antioxidant capacity. In conclusion, Lic A exbibits significant anti-Giardia effects both in vitro and in vivo, suggesting its potential as a promising antiparasitic drug candidate against giardiasis.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"100573"},"PeriodicalIF":4.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of fenbendazole against gastrointestinal nematodes in naturally infected goats in Maputo Province, Mozambique using in vivo, in vitro and molecular assessment.","authors":"Edna F X Guinda, Sonia M S Afonso, Stefan Fiedler, Eric R Morgan, Sabrina Ramünke, Marc Borchert, Alsácia Atanásio, Bettencourt P S Capece, Jürgen Krücken, Georg von Samson-Himmelstjerna","doi":"10.1016/j.ijpddr.2024.100572","DOIUrl":"10.1016/j.ijpddr.2024.100572","url":null,"abstract":"<p><p>Anthelmintic resistance occurs worldwide in strongyles of ruminants but data from low-income countries are sparse and rarely apply most up to date methods, while effects of management practices in these countries are poorly documented. In Mozambique, benzimidazole resistance has been previously reported; the present study followed this up in detail, applying in vivo faecal egg count (FEC) reduction test (FECRT), in vitro egg hatch test (EHT) and molecular deep amplicon sequencing approaches targeting the internal transcribed spacer 2 (ITS-2, nemabiome) and the isotype 1 β-tubulin gene to determine the resistance status on farms and the strongyle species involved. Adult Landim goats (433) from six semi-intensive and ten extensive farms (22-30 animals/farm) from Maputo Province were visited April 2021 to February 2022. Fenbendazole (5 mg/kg bw, Panacur®) was administered orally and FEC determined using Mini-FLOTAC. The eggCounts package was used to calculate FECRs with 90% confidence intervals from paired day 0 and 14 data. In vivo and in vitro tests detected AR on 5/16 (31%) farms. This included 1/10 extensive and 4/6 semi-intensive farms. The odds of finding resistant strongyles on a semi-intensive commercial farm was 40-fold higher than on an extensive farm (p = 0.016, logistic regression). A strong, negative correlation was observed between FECRT and EHT EC₅₀ values (Pearson's R = -0.83, P = 0.001; Cohen's κ coefficient 1.0). Nemabiome data showed that Haemonchus contortus, Trichostrongylus colubriformis and unclassified Oesophagostomum closely related to Oesophagostomum columbianum were most abundant before treatment and in particular H. contortus frequencies increased after treatment. Benzimidazole resistance associated polymorphisms were detected in H. contortus and T. colubriformis. Moreover, there were hints that resistance alleles were present in Trichostrongylus axei and Teladorsagia circumcincta. Farmers should regularly test the efficacy of anthelmintics used and consider more sustainable worm control approaches to reduce selection for resistance.</p>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"27 ","pages":"100572"},"PeriodicalIF":4.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Efficacy of flukicides against Fasciola hepatica and first report of triclabendazole resistance on German sheep farms\" [Int. J. Parasitol. Drugs Drug Resist. 23 (2023) 94-105].","authors":"Alexandra Kahl, Georg von Samson-Himmelstjerna, Christina Helm, Jane Hodgkinson, Diana Williams, Wiebke Weiher, Werner Terhalle, Stephan Steuber, Martin Ganter, Jürgen Krücken","doi":"10.1016/j.ijpddr.2024.100562","DOIUrl":"10.1016/j.ijpddr.2024.100562","url":null,"abstract":"","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":" ","pages":"100562"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antileishmanial and synergic effects of Rhanterium epapposum essential oil and its main compounds alone and combined with glucantime against Leishmania major infection","authors":"Abdullah D. Alanazi ,&nbsp;Areej Jameel Alghabban","doi":"10.1016/j.ijpddr.2024.100571","DOIUrl":"10.1016/j.ijpddr.2024.100571","url":null,"abstract":"<div><div>Cutaneous leishmaniasis (CL) is a widespread disease affecting both humans and animals globally. Currently, common treatments (e.g., glucantime (GC) for CL treatment have many side effects that limit their use. The current experimental study aims to assess the <em>in vitro, in vivo</em>, and potential mechanisms of action of <em>Rhanterium epapposum</em> essential oil (REE) and its main compounds β-Myrcene (MC), camphene (CP), and limonene (LN) alone and in combination against <em>Leishmania major</em>. In vitro effects of REE and its main compounds were evaluated on amastigote forms, infection in macrophages cells stimulation of nitric oxide (NO), and stimulation of the cellular immunity in macrophages. In vivo efficacy of REE and its main constituents was also assessed in mice with CL through evaluating parasite burden, oxidative stress and proinflammatory-related genes. A concentration-dependent reduction in the average number of amastigotes was observed, with statistical significance (p &lt; 0.001); whereas the results revealed synergistic effects when REE, MC and LN were combined with GC. REE and main compounds mainly in combination elicited a dose-dependent elevation in NO production and the expression levels of inducible nitric oxide synthase (iNOS), interferon gamma (IFN-γ), and tumor necrosis factor (TNF-α) genes in macrophages. Notably, mice treated with a combination of REE, MC, and GC showed the complete recovery of CL lesions after 28 days of treatment and resulted in a reduction of tissue malondialdehyde levels and a significant increase (p &lt; 0.001) in the gene expression levels of the antioxidant enzymes. Topical treating CL-infected mice with REE and its main compounds alone particularly in conjunction with GC, significantly increased (p &lt; 0.001) the expression levels of IFN-γ and interleukin (IL-12), while also causing a notable reduction in IL-4 expression. The findings of the current experimental research revealed the high <em>in vitro</em> and <em>in vivo</em> antileishmanial efficacy of REE and its main compounds MC, CP, and LN mainly in combination with GC; which indicated the high synergic effects of these compounds.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100571"},"PeriodicalIF":4.1,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695573","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":"Deep-amplicon sequencing of the complete beta-tubulin gene in Trichuris trichiura before and after albendazole treatment","authors":"Javier Gandasegui ,&nbsp;Berta Grau-Pujol ,&nbsp;Valdemiro Novela ,&nbsp;Osvaldo Muchisse ,&nbsp;Maria Cambra-Pellejà ,&nbsp;Anélsio Cossa ,&nbsp;José Carlos Jamine ,&nbsp;Charfudin Sacoor ,&nbsp;Eric A.T. Brienen ,&nbsp;Francesc Catala-Moll ,&nbsp;Lisette van Lieshout ,&nbsp;María Martínez-Valladares ,&nbsp;Roger Paredes ,&nbsp;José Muñoz ,&nbsp;Stephen R. Doyle","doi":"10.1016/j.ijpddr.2024.100570","DOIUrl":"10.1016/j.ijpddr.2024.100570","url":null,"abstract":"<div><div>Concerns about the emergence of benzimidazole resistance in soil-transmitted helminths (STH) infections, particularly against <em>Trichuris trichiura</em>, have arisen. Previous studies of veterinary nematodes have linked benzimidazole resistance to single-nucleotide polymorphisms (SNPs) at three specific codons in the beta-tubulin gene, but similar associations in STH have not been consistently observed. In this work, we screened the complete beta-tubulin gene previously linked to benzimidazole resistance in <em>T. trichiura</em> by deep-amplicon sequencing to identify genetic variants and associate levels of diversity with drug response to albendazole. We used 99 DNA samples extracted from <em>T. trichiura</em> pooled eggs, previously semi-purified from human stool samples collected in Manhiça district, Mozambique. We obtained a set of 39 amplicons of the complete gene by subjecting the pooled eggs to long-read PCR and subsequently sequencing them. Of those amplicons, 22 and 17 were obtained from stool samples collected before, and 21 days after albendazole treatment, respectively. We observed genetic variation across the whole gene sequence, in both exons and introns; however, none were associated with the previously proposed resistance-associated SNPs, and none were predicted to significantly affect protein function. No significant differences in genetic diversity were observed between pre- and post-treatment samples. Using publicly available genome-wide data, we also analysed a second beta-tubulin isotype in the <em>T. trichiura</em> genome. We focused on detecting the canonical SNPs and assessing for signatures of genetic selection around this second isotype gene. This analysis did not reveal evidence supporting this second isotype's role in anthelmintic resistance. Despite the limitations of our study, such as a small sample size, particularly paired pre- and post-treatment samples (n = 6), or a restricted geographical area, we found no evidence linking either of the two beta-tubulin genes to benzimidazole resistance in <em>T. trichiura</em>, suggesting that genetic markers of drug resistance likely exist outside the beta-tubulin genes.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100570"},"PeriodicalIF":4.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638791","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":"Rapid detection of mutations in the suspected piperaquine resistance gene E415G-exo in Plasmodium falciparum exonuclease via AS‒PCR and RAA with CRISPR/Cas12a","authors":"Huiyin Zhu ,&nbsp;Daiqian Zhu ,&nbsp;Yuting Li ,&nbsp;Yun Li ,&nbsp;Xiaonan Song ,&nbsp;Jinyu Mo ,&nbsp;Long Liu ,&nbsp;Zhixin Liu ,&nbsp;Siqi Wang ,&nbsp;Yi Yao ,&nbsp;He Yan ,&nbsp;Kai Wu ,&nbsp;Wei Wang ,&nbsp;Jianhai Yin ,&nbsp;Min Lin ,&nbsp;Jian Li","doi":"10.1016/j.ijpddr.2024.100568","DOIUrl":"10.1016/j.ijpddr.2024.100568","url":null,"abstract":"<div><div>Malaria remains a major public health concern. The rapid spread of resistance to antimalarial drugs is a major challenge for malaria eradication. Timely and accurate molecular monitoring based on practical detection methods is a critical step toward malaria control and elimination. In this study, two rapid detection techniques, allele-specific PCR (AS<strong>‒</strong>PCR) and recombinase-aided amplification (RAA) combined with CRISPR/Cas12a, were established, optimized and assessed to detect single nucleotide polymorphisms in the <em>Plasmodium falciparum exonuclease</em> (<em>Pfexo</em>) gene related to suspected piperaquine resistance. Moreover, phosphorothioate and artificial mismatches were introduced into the allele-specific primers for AS<strong>‒</strong>PCR, and crRNA-mismatched bases were introduced into the RAA<strong>‒</strong>CRISPR/Cas12a assay because crRNAs designed according to conventional rules fail to discriminate genotypes. As a result, the detection limits of the AS<strong>‒</strong>PCR and RAA<strong>‒</strong>CRISPR/Cas12a assays were 10⁴ copies/μL and 10³ copies/μL, respectively. The detection threshold for dried blood spots was 100<strong>‒</strong>150 parasites/μL, with no cross-reactivity against other genotypes. The average cost of AS<strong>‒</strong>PCR is approximately $1 per test and takes 2<strong>–</strong>3 h, whereas that of the RAA<strong>‒</strong>CRISPR/Cas12a system is approximately $7 per test and takes 1 h or less. Therefore, we provide more options for testing single nucleotide polymorphisms in the <em>Pfexo</em> gene, considering economic conditions and the availability of instruments, equipment, and reagents, which can contribute to the molecular monitoring of antimalarial resistance.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100568"},"PeriodicalIF":4.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545291","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":"Profile of molecular markers of Sulfadoxine-Pyrimethamine-resistant Plasmodium falciparum in individuals living in southern area of Brazzaville, Republic of Congo","authors":"Jean Claude Djontu ,&nbsp;Marcel Tapsou Baina ,&nbsp;Jacque Dollon Mbama Ntabi ,&nbsp;Abel Lissom ,&nbsp;Dieu Merci Umuhoza ,&nbsp;Naura veil Assioro Doulamo ,&nbsp;Christevy Jeanney Vouvoungui ,&nbsp;Reauchelvy Kamal Boumpoutou ,&nbsp;Alain Maxime Mouanga ,&nbsp;Etienne Nguimbi ,&nbsp;Francine Ntoumi","doi":"10.1016/j.ijpddr.2024.100569","DOIUrl":"10.1016/j.ijpddr.2024.100569","url":null,"abstract":"<div><h3>Background</h3><div>Although the seasonal and perennial malaria chemopreventions are not implemented in the Republic of Congo, resistance to Sulfadoxine-pyrimethamine (SP) threatens the intermittent preventive treatment during pregnancy (IPTp-SP) and others treatments using the drug. The objective of this study was to determine the prevalence of molecular markers of <em>P.falciparum</em> resistance to SP in individuals with microscopic malaria infection in the south of Brazzaville.</div></div><div><h3>Methods</h3><div>Two parallel surveys (health facilities and community-based cross sectional studies) were carried out in urban and rural areas in southern Brazzaville. Between March and October 2021, blood samples were collected from 328 <em>P. falciparum</em> microscopic positive individuals (1–83 years old, and sex ratio female/male of 1.1) to characterize <em>dhfr</em> and <em>dhps</em> genes involved in the <em>P.falciparum</em> resistance to SP. Restriction Fragment Length Polymorphism PCR was used for the detection of mutations within these parasite genes.</div></div><div><h3>Results</h3><div>High prevalence of mutations was reported within <em>Pfdhfr</em> gene: N51<strong>I</strong>; 328/328 (100%) ratio (prevalence) [95 CI uncertainty], C59<strong>R</strong>; 317/328 (96.6 %) [94.1–98.1%], S108<strong>N;</strong> 326/326 (100%), N164<strong>L;</strong> 3/326 (0.9%) [0.3–2.7%], and <em>Pfdhps</em> gene: A437<strong>G</strong>; 292/327 (89.3%) [85.5–92.2%], K540<strong>E</strong>; 140/327(42.8 %) [37.6–48.2%], A581<strong>G</strong>; 136/325 (41.8%) [36.6–42.3%]. The quintuple mutant (N51<strong>I</strong> + C59<strong>R</strong> + S108<strong>N +</strong> A437<strong>G</strong> + K540<strong>E)</strong> and sextuple mutant haplotypes (N51<strong>I</strong> + C59<strong>R</strong> + S108<strong>N +</strong> A437<strong>G</strong> + K540<strong>E +</strong> A581<strong>G)</strong> were reported for 11/144 (7.6%) [4.3–13.2%] and 5/144 (3.4%) [1.5–7.9%]) of the participants respectively. The K540<strong>E</strong> and A437<strong>G</strong> mutants were more prevalent in the rural community; 81/139 (58.3%) [50.0–66.1%] and 135/139 (97.1%) [92.8–98.9%] respectively) than in the urban community; 21/50 (46.3%) [33.7–59.4%] and 47/54(87.0%) [75.6–93.6%] (p = 0.004 and p˂0.0001 respectively)</div></div><div><h3>Conclusion</h3><div>These results indicate high prevalence of SP resistance mutations within the <em>dhfr</em> and <em>dhps</em> genes of <em>P. falciparum</em> isolates circulating in study sites, which may limit the efficacy of treatments using SP in these settings.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100569"},"PeriodicalIF":4.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564408","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":"Yeast-based assay to identify inhibitors of the malaria parasite sodium phosphate uptake transporter as potential novel antimalarial drugs","authors":"Joseph M. Sweeney ,&nbsp;Ian M. Willis ,&nbsp;Myles H. Akabas","doi":"10.1016/j.ijpddr.2024.100567","DOIUrl":"10.1016/j.ijpddr.2024.100567","url":null,"abstract":"<div><div>Malaria affects almost 250 million people annually and continues to be a significant threat to global public health. Infection with protozoan parasites from the genus <em>Plasmodium</em> causes malaria. The primary treatment for malaria is artemisinin-based combination therapies (ACTs). The spread of ACT-resistant parasites has undermined efforts to control and eradicate malaria. Thus, it is crucial to identify new targets for the development of novel antimalarial drugs. Phosphate is an essential nutrient for all cells. The <em>Plasmodium falciparum</em> genome encodes a single sodium-coupled inorganic phosphate transporter named PfPiT that is essential for parasite proliferation in the asexual blood stage. Thus, PfPiT inhibitors may be promising antimalarial drugs. Like <em>Plasmodium</em>, yeast requires phosphate to grow. We developed a <em>Saccharomyces cerevisiae</em> based growth assay to identify inhibitors of PfPiT. Genome editing was used to create a yeast strain where PfPiT was the only phosphate transporter. Using a radioactive [³²P]phosphate uptake assay, the measured phosphate K_m for PfPiT in yeast was 56 ± 7 μM in 1 mM NaCl at pH 7.4. The K_m decreased to 24 ± 3 μM in 25 mM NaCl consistent with it being a Na⁺ coupled cotransporter. Conditions under which yeast growth was dependent on phosphate uptake mediated by PfPiT were identified and a 22-h growth assay was developed to screen for PfPiT inhibitors. In a screen of 21 compounds, two compounds were identified that inhibited the growth of the PfPiT strain but not that of the parental strain expressing Pho84, one of the five endogenous yeast phosphate transporters. Radioactive phosphate uptake experiments confirmed inhibition of phosphate uptake by the two compounds. The growth inhibition assay provides a simple and inexpensive approach to screen a large compound library for PfPiT inhibitors that may serve as starting points for the development of novel antimalarial drugs.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100567"},"PeriodicalIF":4.1,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499836","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":"Comparative proteomic analysis of metronidazole-sensitive and resistant Trichomonas vaginalis suggests a novel mode of metronidazole action and resistance","authors":"Anna-Lena Mayr ,&nbsp;Ana Paunkov ,&nbsp;Karin Hummel ,&nbsp;Ebrahim Razzazi-Fazeli ,&nbsp;David Leitsch","doi":"10.1016/j.ijpddr.2024.100566","DOIUrl":"10.1016/j.ijpddr.2024.100566","url":null,"abstract":"<div><div>The microaerophilic parasite <em>Trichomonas vaginalis</em> occurs worldwide and causes inflammation of the urogenital tract, especially in women. With 156 million infections annually, trichomoniasis is the most prevalent non-viral sexually transmitted disease. Trichomoniasis is treated with 5-nitroimidazoles, especially metronidazole, which are prodrugs that have to be reduced at their nitro group to be activated. Resistance rates to metronidazole have remained comparably low, but they can be higher in certain areas leading to an increase of refractory cases. Metronidazole resistance in <em>T</em>. <em>vaginalis</em> can develop <em>in vivo</em> in clinical isolates, or it can be induced in the laboratory. Both types of resistance share certain characteristics but differ with regard to the dependence of ambient oxygen to become manifest. Although several candidate factors for metronidazole resistance have been described in the past, e.g. pyruvate:ferredoxin oxidoreductase and ferredoxin or thioredoxin reductase, open questions regarding their role in resistance have remained.</div><div>In order to address these questions, we performed a proteomic study with metronidazole-sensitive and –resistant laboratory strains, as well as with clinical strains, in order to identify factors causative for resistance. The list of proteins consistently associated with resistance was surprisingly short. Resistant laboratory and clinical strains only shared the downregulation of flavin reductase 1 (FR1), an enzyme previously identified to be involved in resistance. Originally, FR1 was believed to be an oxygen scavenging enzyme, but here we identified it as a ferric iron reductase which produces ferrous iron. Based on this finding and on further experimental evidence as presented herein, we propose a novel mechanism of metronidazole activation which is based on ferrous iron binding to proteins, thereby rendering them susceptible to complex formation with metronidazole. Upon resolution of iron-protein-metronidazole complexes, metronidazole radicals are formed which quickly react with thiols or proteins in the direct vicinity, leading to breaks in the peptide backbone.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100566"},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377890","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 artemisinin-resistant falciparum malaria parasites, mitochondrial metabolic pathways are essential for survival but not those of apicoplast","authors":"Manel Ouji ,&nbsp;Thibaud Reyser ,&nbsp;Yoshiki Yamaryo-Botté ,&nbsp;Michel Nguyen ,&nbsp;David Rengel ,&nbsp;Axelle Dutreuil ,&nbsp;Marlène Marcellin ,&nbsp;Odile Burlet-Schiltz ,&nbsp;Jean-Michel Augereau ,&nbsp;Michael K. Riscoe ,&nbsp;Lucie Paloque ,&nbsp;Cyrille Botté ,&nbsp;Françoise Benoit-Vical","doi":"10.1016/j.ijpddr.2024.100565","DOIUrl":"10.1016/j.ijpddr.2024.100565","url":null,"abstract":"<div><div>Emergence and spread of parasite resistance to artemisinins, the first-line antimalarial therapy, threaten the malaria eradication policy. To identify therapeutic targets to eliminate artemisinin-resistant parasites, the functioning of the apicoplast and the mitochondrion was studied, focusing on the fatty acid synthesis type II (FASII) pathway in the apicoplast and the electron transfer chain in the mitochondrion. A significant enrichment of the FASII pathway among the up-regulated genes in artemisinin-resistant parasites under dihydroartemisinin treatment was found, in agreement with published transcriptomic data. However, using GC-MS analyzes of fatty acids, we demonstrated for the first time that the FASII pathway is non-functional, ruling out the use of FASII inhibitors to target artemisinin-resistant parasites. Conversely, by assessing the modulation of the oxygen consumption rate, we evidenced that mitochondrial respiration remains functional and flexible in artemisinin-resistant parasites and even at the quiescent stage. Two novel compounds targeting electron transport chain (ELQ300, ELQ400) efficiently killed quiescent artemisinin-resistant parasites. Therefore, mitochondrial respiration represents a key target for the elimination of artemisinin-resistant persistent <em>Plasmodium falciparum</em> parasites.</div></div>","PeriodicalId":13775,"journal":{"name":"International Journal for Parasitology: Drugs and Drug Resistance","volume":"26 ","pages":"Article 100565"},"PeriodicalIF":4.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}