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Jing QD, A JD, Liu LX, Fan HN. Current status of drug therapy for alveolar echinococcosis. World J Hepatol 2024; 16:1243-1254. [PMID: 39606163 PMCID: PMC11586754 DOI: 10.4254/wjh.v16.i11.1243] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/13/2024] [Accepted: 10/15/2024] [Indexed: 11/06/2024] Open
Abstract
Alveolar echinococcosis (AE) is a chronic zoonotic parasitic disease caused by infection with Echinococcus multilocularis. AE is associated with a high mortality rate and poses a significant threat to human health. The primary treatment for AE is surgical resection of the lesions; however, owing to its long incubation period and insidious disease progression, many patients are diagnosed only after the onset of complications such as liver cirrhosis, jaundice, and portal hypertension, which preclude curative surgical intervention. For patients who are unwilling or unable to undergo surgery, lifelong administration of anti-AE medications is necessary. Benzimidazole compounds, such as albendazole and mebendazole, are the current mainstays of treatment, offering good efficacy. Nevertheless, these medications primarily inhibit parasite proliferation rather than eradicate the infection, and their long-term use can lead to significant drug-related toxic effects. Consequently, there is an urgent need to develop new therapeutic strategies that convey better efficacy and reduce the adverse effects associated with current treatments. Recent advancements in AE therapy include novel synthetic compounds such as antiviral agents, antibiotics, antineoplastic agents, immunosuppressants, and antiangiogenic agents, as well as natural compounds derived from traditional Chinese and Tibetan medicine. These new drugs show promising clinical potential because they interfere with parasitic metabolic pathways and cellular structures. This review aims to discuss recent research on AE drug therapy, including mechanisms of action, dosing regimens, signalling pathways, and therapeutic outcomes, with a goal of providing new insights and directions for the development of anti-AE drugs and summarizing current advancements in AE pharmacotherapy.
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Affiliation(s)
- Qin-Dong Jing
- Department of General Surgery, Qinghai Provincial People's Hospital, Xining 810000, Qinghai Province, China
- School of Clinical Medicine, Qinghai University, Xining 810000, Qinghai Province, China
| | - Ji-De A
- Department of Hepatic Hydatidosis, Qinghai Provincial People's Hospital, Xining 810007, Qinghai Province, China
| | - Lin-Xun Liu
- Department of General Surgery, Qinghai Provincial People's Hospital, Xining 810000, Qinghai Province, China
| | - Hai-Ning Fan
- Department of Hepatobiliary and Pancreatic Surgery, Qinghai Province Research Key Laboratory for Echinococcosis, Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China.
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2
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Autier B, Robert-Gangneux F, Dion S. Chemotherapy for the treatment of alveolar echinococcosis: Where are we? Parasite 2024; 31:56. [PMID: 39311470 PMCID: PMC11418394 DOI: 10.1051/parasite/2024055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 08/23/2024] [Indexed: 09/26/2024] Open
Abstract
Alveolar echinococcosis (AE) is a severe liver disease due to infection with the Echinococcus multilocularis larval stage, called the metacestode. Management of AE is based on benzimidazole chemotherapy (albendazole or mebendazole), associated with surgery when possible. Benzimidazoles are the only compounds recommended for the treatment of AE; however, these are parasitostatic, which means that the parasite can resume growth when treatment is interrupted. Also, benzimidazoles can cause liver dysfunction which may prevent their use. Numerous drugs have been reported to have in vitro activity against E. multilocularis, but few had satisfactory in vivo activity, and none were clearly more effective than benzimidazoles. These drugs belong to various therapeutic categories including anti-infective agents (e.g. amphotericin B, mefloquine, pentamidine derivatives), anti-neoplastic compounds (e.g. imatinib, nilotinib, bortezomib), plant-extracted compounds (e.g. thymol, crocin, carvacrol) and others (e.g. metformin, verapamil, thiaclopride). These treatments are generally of limited interest due to their toxicity, their unfavorable pharmacokinetics, or the scarcity of studies involving humans. Apart from benzimidazoles, only amphotericin B, mefloquine and nitazoxanide have been reported to be used for human AE treatment, with unsatisfactory results. Few studies have aimed at developing innovative strategies for AE drug therapy, such as vectorization of drugs using nanoparticles. Altogether, this review emphasizes the urgent need for new therapeutic strategies in AE management, for which there is currently no curative chemotherapy.
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Affiliation(s)
- Brice Autier
- Université de Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085 Rennes France
| | - Florence Robert-Gangneux
- Université de Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085 Rennes France
| | - Sarah Dion
- Université de Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085 Rennes France
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3
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Dalhoff A. Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks? Infection 2021; 49:29-56. [PMID: 33367978 PMCID: PMC7851017 DOI: 10.1007/s15010-020-01536-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 10/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
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Affiliation(s)
- Axel Dalhoff
- Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany.
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Zhang L, He J, Bai L, Ruan S, Yang T, Luo Y. Ribosome-targeting antibacterial agents: Advances, challenges, and opportunities. Med Res Rev 2021; 41:1855-1889. [PMID: 33501747 DOI: 10.1002/med.21780] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/08/2020] [Accepted: 12/19/2020] [Indexed: 02/05/2023]
Abstract
Ribosomes, which synthesize proteins, are critical organelles for the survival and growth of bacteria. About 60% of approved antibiotics discovered so far combat pathogenic bacteria by targeting ribosomes. However, several issues, such as drug resistance and toxicity, have impeded the clinical use of ribosome-targeting antibiotics. Moreover, the complexity of the bacteria ribosome structure has retarded the discovery of new ribosome-targeting agents that are considered as the key to the drug-resistance and toxicity. To deal with these challenges, efforts such as medicinal chemistry optimization, combination treatment, and new drug delivery system have been developed. But not enough, the development of structural biology and new screening methods bring powerful tools, such as cryo-electron microscopy technology, advanced computer-aided drug design, and cell-free in vitro transcription/translation systems, for the discovery of novel ribosome-targeting antibiotics. Thus, in this paper, we overview the research on different aspects of bacterial ribosomes, especially focus on discussing the challenges in the discovery of ribosome-targeting antibacterial drugs and advances made to address issues such as drug-resistance and selectivity, which, we believe, provide perspectives for the discovery of novel antibiotics.
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Affiliation(s)
- Laiying Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Jun He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Lang Bai
- Center of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Shihua Ruan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Tao Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.,Laboratory of Human Diseases and Immunotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.,Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Youfu Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China
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Hemphill A, Rufener R, Ritler D, Dick L, Lundström‐Stadelmann B. Drug Discovery and Development for the Treatment of Echinococcosis, Caused by the Tapeworms
Echinococcus granulosus
and
Echinococcus multilocularis. METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2019:253-287. [DOI: 10.1002/9783527808656.ch10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Drug-Induced Mitochondrial Toxicity in the Geriatric Population: Challenges and Future Directions. BIOLOGY 2019; 8:biology8020032. [PMID: 31083551 PMCID: PMC6628177 DOI: 10.3390/biology8020032] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 02/04/2019] [Accepted: 02/12/2019] [Indexed: 12/22/2022]
Abstract
Mitochondrial function declines with age, leading to a variety of age-related diseases (metabolic, central nervous system-related, cancer, etc.) and medication usage increases with age due to the increase in diseases. Drug-induced mitochondrial toxicity has been described for many different drug classes and can lead to liver, muscle, kidney and central nervous system injury and, in rare cases, to death. Many of the most prescribed medications in the geriatric population carry mitochondrial liabilities. We have demonstrated that, over the past decade, each class of drugs that demonstrated mitochondrial toxicity contained drugs with both more and less adverse effects on mitochondria. As patient treatment is often essential, we suggest using medication(s) with the best safety profile and the avoidance of concurrent usage of multiple medications that carry mitochondrial liabilities. In addition, we also recommend lifestyle changes to further improve one’s mitochondrial function, such as weight loss, exercise and nutrition.
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Lundström-Stadelmann B, Rufener R, Ritler D, Zurbriggen R, Hemphill A. The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis. Food Waterborne Parasitol 2019; 15:e00040. [PMID: 32095613 PMCID: PMC7034016 DOI: 10.1016/j.fawpar.2019.e00040] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/06/2019] [Accepted: 02/12/2019] [Indexed: 02/06/2023] Open
Abstract
The lethal disease alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical treatment of AE relies on albendazole and mebendazole, with the caveat that these compounds are not parasiticidal. Drugs have to be taken for a prolonged period of time, often life-long, which can cause adverse effects and reduces the patients' quality of life. In some individuals, benzimidazoles are inactive or cause toxicity, leading to treatment discontinuation. Alternatives to benzimidazoles are urgently needed. Over the recent years, in vivo and in vitro models for low-to-medium throughput drug discovery against AE have been set in place. In vitro drug tests include the phosphoglucose-isomerase (PGI) assay to measure physical damage induced to metacestodes, and viability assays to assess parasiticidal activity against metacestodes and stem cells. In vitro models are also employed for studies on mechanisms of action. In vivo models are thus far based on rodents, mainly mice, and benefits could be gained in future by comparative approaches in naturally infected dogs or captive monkeys. For the identification of novel drugs against AE, a rare disease with a low expected market return, drug-repurposing is the most promising strategy. A variety of chemically synthesized compounds as well as natural products have been analyzed with respect to in vitro and/or in vivo activities against AE. We here review and discuss the most active of these compounds including anti-infective compounds (benzimidazoles, nitazoxanide, amphotericin B, itraconazole, clarithromycin, DB1127, and buparvaquone), the anti-infective anti-malarials (artemisinin, ozonids, mefloquine, and MMV665807) and anti-cancer drugs (isoflavones, 2-methoxyestradiol, methotrexate, navelbine, vincristine, kinase inhibitors, metallo-organic ruthenium complexes, bortezomib, and taxanes). Taking into account the efficacy as well as the potential availability for patients, the most promising candidates are new formulations of benzimidazoles and mefloquine. Future drug-repurposing approaches should also target the energy metabolism of E. multilocularis, in particular the understudied malate dismutation pathway, as this offers an essential target in the parasite, which is not present in mammals.
Benzimidazoles are used to treat AE, but new drugs are needed. New drugs against AE can be identified by drug repurposing. Drugs against other infectious diseases and cancer can be repurposed against AE. Most promising are new formulations of benzimidazoles and mefloquine. Future approaches should include targeting the energy metabolism of the parasite.
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Affiliation(s)
- Britta Lundström-Stadelmann
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Reto Rufener
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Dominic Ritler
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Raphael Zurbriggen
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
| | - Andrew Hemphill
- Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012 Bern, Switzerland
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8
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Joekel DE, Lundström-Stadelmann B, Müllhaupt B, Hemphill A, Deplazes P. Evaluation of kinase-inhibitors nilotinib and everolimus against alveolar echinococcosis in vitro and in a mouse model. Exp Parasitol 2018; 188:65-72. [PMID: 29625098 DOI: 10.1016/j.exppara.2018.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/07/2018] [Accepted: 04/02/2018] [Indexed: 11/19/2022]
Abstract
Infection with the larval stage (metacestode) of the fox tapeworm Echinococcus multilocularis leads to a primary hepatic disease referred to as alveolar echinococcosis (AE). The progressive disease can be lethal if untreated. In cases where complete parasite resection by surgery is not feasible, the current treatment regimens of AE consist of chemotherapy with the parasitostatic benzimidazoles albendazole or mebendazole over decades. Kinase-inhibitors currently administered in various cancer treatments are of increasing interest also as anti-parasitic drugs due to previous promising in vitro results. In order to search for novel drug targets and treatment regimens, nilotinib (AMN107; Tasigna®), an Abl-tyrosine kinase inhibitor and everolimus (RAD001; Afinitor®), a serine/threonine-kinase inhibitor, were tested for their treatment efficacy against metacestode vesicles of E. multilocularis in vitro and in BALB/c mice. In vitro treatment with 200 μM nilotinib caused drug-induced alterations after 12 days, and everolimus exerted parasite damage at concentrations dosing from 40 to 100 μM after 5 and 12 days of in vitro exposure. Nilotinib (100 mg/kg) + erythromycin (to increase nilotinib plasma levels: 10 mg/kg intraperitoneal) or everolimus (5 mg/kg) were formulated in honey and administered daily for three weeks and subsequently twice a week for an additional three weeks in experimentally infected mice. Treatments did not result in any reduction of parasite growth compared to untreated control groups, whereas oral treatment with albendazole (200 mg/kg) was highly effective. Combined application of the kinase-inhibitors with albendazole did not lead to a synergistic or additive treatment efficacy compared to albendazole treatment alone. These results show that neither nilotinib nor everolimus represent valuable alternatives to the current treatment regimens against AE.
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Affiliation(s)
- Deborah E Joekel
- Institute of Parasitology, Vetsuisse Faculty, University of Zurich, Switzerland
| | | | - Beat Müllhaupt
- Division of Gastroenterology and Hepatology, University Hospital of Zurich, Switzerland
| | - Andrew Hemphill
- Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland
| | - Peter Deplazes
- Institute of Parasitology, Vetsuisse Faculty, University of Zurich, Switzerland.
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9
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Lleonart ME, Grodzicki R, Graifer DM, Lyakhovich A. Mitochondrial dysfunction and potential anticancer therapy. Med Res Rev 2017; 37:1275-1298. [DOI: 10.1002/med.21459] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 06/13/2017] [Accepted: 06/19/2017] [Indexed: 12/11/2022]
Affiliation(s)
| | - Robert Grodzicki
- Thomas Steitz Laboratory; Department of Molecular Biophysics & Biochemistry, Center for Structural Biology, Howard Hughes Medical Institute; Yale University; New Haven Connecticut
| | | | - Alex Lyakhovich
- Oncology Program; Vall D'Hebron Research Institute; Barcelona Spain
- Institute of Molecular Biology and Biophysics, Novosibirsk; Russia
- International Clinical Research Center and St. Anne's University Hospital Brno; Czech Republic
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10
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Clarithromycin Suppresses Chloride Channel Accessory 1 and Inhibits Interleukin-13-Induced Goblet Cell Hyperplasia in Human Bronchial Epithelial Cells. Antimicrob Agents Chemother 2016; 60:6585-6590. [PMID: 27550358 DOI: 10.1128/aac.01327-16] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/14/2016] [Indexed: 01/01/2023] Open
Abstract
Activation of the interleukin-13 (IL-13) receptor leads to signal transducer and activator of transcription 6 (STAT6) activation and subsequent induction of SAM pointed domain containing ETS transcription factor (SPDEF) and chloride channel accessory 1 (CLCA1), increasing secretion of the gel-forming mucin MUC5AC. Activation of the epidermal growth factor receptor (EGFR) also leads to MUC5AC production via extracellular signal-regulated kinase (ERK1/2). We examined the effect of clarithromycin IL-13 signaling leading to production. Normal human bronchial epithelial (NHBE) cells were grown for 14 days at an air-liquid interface (ALI) with IL-13 and/or clarithromycin. Histochemical analysis was performed using hematoxylin and eosin (HE) staining and MUC5AC immunostaining. MUC5AC, SPDEF, and CLCA1 mRNA expression were evaluated by real-time PCR. Western analysis was used to assess phosphorylation of STAT6 and ERK1/2. Clarithromycin decreased IL-13-induced goblet cell hyperplasia and MUC5AC mRNA expression in a dose-dependent manner. Clarithromycin decreased IL-13-stimulated SPDEF and CLCA1 mRNA expression in a dose-dependent manner, and at 32 μg/ml CLCA1 was profoundly decreased (P < 0.001). Although clarithromycin had no effect on STAT6 phosphorylation induced by IL-13, it decreased constitutive phosphorylation of ERK1/2 (P < 0.05).
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Hemphill A, Stadelmann B, Rufener R, Spiliotis M, Boubaker G, Müller J, Müller N, Gorgas D, Gottstein B. Treatment of echinococcosis: albendazole and mebendazole--what else? ACTA ACUST UNITED AC 2014; 21:70. [PMID: 25526545 PMCID: PMC4271654 DOI: 10.1051/parasite/2014073] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 12/11/2014] [Indexed: 01/14/2023]
Abstract
The search for novel therapeutic options to cure alveolar echinococcosis (AE), due to the metacestode of Echinococcus multilocularis, is ongoing, and these developments could also have a profound impact on the treatment of cystic echinococcosis (CE), caused by the closely related Echinococcus granulosus s.l. Several options are being explored. A viable strategy for the identification of novel chemotherapeutically valuable compounds includes whole-organism drug screening, employing large-scale in vitro metacestode cultures and, upon identification of promising compounds, verification of drug efficacy in small laboratory animals. Clearly, the current focus is targeted towards broad-spectrum anti-parasitic or anti-cancer drugs and compound classes that are already marketed, or that are in development for other applications. The availability of comprehensive Echinococcus genome information and gene expression data, as well as significant progress on the molecular level, has now opened the door for a more targeted drug discovery approach, which allows exploitation of defined pathways and enzymes that are essential for the parasite. In addition, current in vitro and in vivo models that are used to assess drug efficacy should be optimized and complemented by methods that give more detailed information on the host-parasite interactions that occur during drug treatments. The key to success is to identify, target and exploit those parasite molecules that orchestrate activities essential to parasite survival.
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Affiliation(s)
- Andrew Hemphill
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Britta Stadelmann
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Reto Rufener
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Markus Spiliotis
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Ghalia Boubaker
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Joachim Müller
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Norbert Müller
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
| | - Daniela Gorgas
- Department of Clinical Veterinary Medicine, Clinical Radiology, Bremgartenstrasse 109a, 3012 Berne, Switzerland
| | - Bruno Gottstein
- Vetsuisse Faculty, Institute of Parasitology, University of Berne, Länggass-Strasse 122, 3012 Berne, Switzerland
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In vitro efficacy of triclabendazole and clorsulon against the larval stage of Echinococcus multilocularis. Parasitol Res 2013; 112:1655-60. [PMID: 23455934 DOI: 10.1007/s00436-013-3321-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 01/24/2013] [Indexed: 01/27/2023]
Abstract
Alveolar echinococcosis (AE) caused by the cestode Echinococcus multilocularis (E. multilocularis) is endemic in wide areas of the Northern hemisphere. Untreated AE progresses and leads to death in more than 90% of cases. Until the advent of benzimidazoles, no antihelminthic drugs were available to cure AE. Benzimidazoles have greatly improved the prognosis of patients with AE. However, benzimidazoles have only a parasitostatic effect on E. multilocularis. Albendazole (ABZ) must sometimes be withdrawn because of adverse events. Alternative drugs are urgently needed. The antihelminthic triclabendazole (TCZ) and clorsulon (CLS) are more effective than ABZ to cure infections by the liver flukes Fasciola spp. The efficacy of TCZ and CLS was investigated on an in vitro culture of E. multilocularis larval tissue. E. multilocularis vesicles were evaluated for their morphology before and after adding TCZ, TCZ sulfoxide (TCZSX) and CLS to the larval tissue culture. TCZ at the concentrations of 20 μg/ml culture solution led to maximum vesicle damage within 12 days and of 25 μg/ml within 13 days, and TCZSX at the concentrations of 20 μg/ml within 20 days and of 25 μg/ml within 14 days. Contrary, CLS added at 5, 10 and 15 μg/ml to culture solution did not lead to any vesicle damage. TCZ is a promising further candidate drug for the treatment of AE.
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13
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Characterization of TsMRP-L28, a mitochondrial ribosomal protein L28 from the parasitic nematode Trichinella spiralis. Gene 2013; 512:496-504. [DOI: 10.1016/j.gene.2012.10.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Revised: 06/06/2012] [Accepted: 10/10/2012] [Indexed: 11/20/2022]
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Abstract
Quinine (QN) and quinidine (QND) have been commonly used as effective and affordable antimalarials for over many years. Quinine primarily is used for severe malaria treatment. However, plasmodia resistance to these drugs and poor patient compliance limits their administration to the patients. The declining sensitivity of the parasite to the drugs can thus be dealt with by combining with a suitable partner drug. In the present study QN/QND was assessed in combination with clarithromycin (CLTR), an antibiotic of the macrolide family. In vitro interactions of these drugs with CLTR against Plasmodium falciparum (P. falciparum) have shown a synergistic response with mean sum fractional inhibitory concentrations (ΣFICs) of ≤1 (0.85 ± 0.11 for QN + CLTR and 0.64 ± 0.09 for QND + CLTR) for all the tested combination ratios. Analysis of this combination of QN/QND with CLTR in mouse model against Plasmodium yoelii nigeriensis multi-drug resistant (P. yoelii nigeriensis MDR) showed that a dose of 200 mg/kg/day for 4 days of QN or QND produces 100% curative effect with 200 mg/kg/day for 7 days and 150 mg/kg/day for 7 days CLTR respectively, while the same dose of individual drugs could produce only up to a maximum 20% cure. It is postulated that CLTR, a CYP3A4 inhibitor, might have caused reduced CYP3A4 activity leading to increased plasma level of the QN/QND to produce enhanced antimalarial activity. Further, parasite apicoplast disruption by CLTR synergies the antimalarial action of QN and QND.
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Clarithromycin, a cytochrome P450 inhibitor, can reverse mefloquine resistance in Plasmodium yoelii nigeriensis- infected Swiss mice. Parasitology 2011; 138:1069-76. [PMID: 21756423 DOI: 10.1017/s0031182011000850] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
During the last 2 decades there have been numerous reports of the emergence of mefloquine resistance in Southeast Asia and nearly 50% resistance is reported in Thailand. A World Health Organization report (2001) considers mefloquine as an important component of ACT (artesunate+mefloquine) which is the first line of treatment for the control of uncomplicated/multi-drug resistant (MDR) Plasmodium falciparum malaria. In view of the emergence of resistance towards this drug, it is proposed to develop new drug combinations to prolong the protective life of this drug. Prior studies have suggested that mefloquine resistance can be overcome by a variety of agents such as ketoconazole, cyproheptadine, penfluridol, Icajine and NP30. The present investigation reports that clarithromycin (CLTR), a new macrolide, being a potent inhibitor of Cyt. P450 3A4, can exert significant resistance reversal action against mefloquine resistance of plasmodia. Experiments were carried out to find out the curative dose of CLTR against multi-drug resistant P. yoelii nigeriensis. Mefloquine (MFQ) and clarithromycin (CLTR) combinations have been used for the treatment of this MDR parasite. Different dose combinations of these two drugs were given to the infected mice on day 0 (prophylactic) and day 1 with established infection (therapeutic) to see the combined effect of these combinations against the MDR malaria infection. With a dose of 32 mg/kg MFQ and 225 mg/kg CLTR, 100% cure was observed, while in single drug groups, treated with MFQ or CLTR, the cure was zero and 40% respectively. Therapeutically, MFQ and CLTR combinations 32+300 mg/kg doses cleared the established parasitaemia on day 10. Single treatment with MFQ or CLTR showed considerable suppression of parasitaemia on day 14 but neither was curative. Follow-up of therapeutically treated mice showed enhanced anti-malarial action as reflected by their 100% clearance of parasitaemia. The present study reveals that CLTR is a useful antibiotic to be used as companion drug with mefloquine in order to overcome mefloquine resistance in plasmodia.
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16
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Hobbie SN, Kaiser M, Schmidt S, Shcherbakov D, Janusic T, Brun R, Böttger EC. Genetic reconstruction of protozoan rRNA decoding sites provides a rationale for paromomycin activity against Leishmania and Trypanosoma. PLoS Negl Trop Dis 2011; 5:e1161. [PMID: 21629725 PMCID: PMC3101183 DOI: 10.1371/journal.pntd.0001161] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 03/17/2011] [Indexed: 12/04/2022] Open
Abstract
Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compounds bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal activity and is used for the treatment of parasitic infections, e.g. by Leishmania spp. The precise drug target is, however, unclear; in particular whether aminoglycoside antibiotics target the cytosolic and/or the mitochondrial protozoan ribosome. To establish an experimental model for the study of protozoan decoding-site function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences. Relating the results from in-vitro ribosomal assays to that of in-vivo aminoglycoside activity against Trypanosoma brucei, as assessed in cell cultures and in a mouse model of infection, we conclude that aminoglycosides affect cytosolic translation while the mitochondrial ribosome of trypanosomes is not a target for aminoglycoside antibiotics. Rational design of novel therapeutics relies on the knowledge and understanding of potential drug targets. Historically, the majority of therapeutics have not been rationally designed, but empirically discovered. Paromomycin, an aminoglycoside with antibacterial activity, has been found to show considerable activity against leishmaniasis, a disease caused by the protozoan parasite Leishmania. However, the mechanisms of aminoglycoside action against protozoan parasites have in part remained unclear. In this study we demonstrate that the cytosolic ribosome is the preferred drug target, and that the mitochondrial ribosome does not contribute to the antiprotozoal activity of aminoglycosides. As the cytosolic ribosome of Trypanosoma, the causative agent of sleeping sickness and Chagas disease, resembles that of Leishmania, we tested the efficacy of paromomycin against Trypanosoma. We found that paromomycin not only inhibits the growth of Trypanosoma in culture, but also suppresses trypanosomiasis in a mouse infection model. Our results point to the cytosolic ribosome as a promising drug target for antiprotozoal drug development.
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MESH Headings
- Animals
- Antiprotozoal Agents/pharmacology
- Disease Models, Animal
- Female
- Leishmania/drug effects
- Mice
- Parasitic Sensitivity Tests
- Paromomycin/pharmacology
- Protein Biosynthesis/drug effects
- RNA, Bacterial/genetics
- RNA, Bacterial/metabolism
- RNA, Protozoan/genetics
- RNA, Protozoan/metabolism
- RNA, Ribosomal/genetics
- RNA, Ribosomal/metabolism
- Recombination, Genetic
- Rodent Diseases/drug therapy
- Rodent Diseases/parasitology
- Trypanosoma brucei brucei/drug effects
- Trypanosomiasis, African/drug therapy
- Trypanosomiasis, African/parasitology
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Affiliation(s)
- Sven N. Hobbie
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Marcel Kaiser
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Sebastian Schmidt
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Dmitri Shcherbakov
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Tanja Janusic
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
| | - Reto Brun
- Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland
- University of Basel, Basel, Switzerland
| | - Erik C. Böttger
- Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
- * E-mail:
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17
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Combined albendazole and amphotericin B against Echinococcus multilocularis in vitro. Acta Trop 2010; 115:270-4. [PMID: 20412782 DOI: 10.1016/j.actatropica.2010.04.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Revised: 03/22/2010] [Accepted: 04/14/2010] [Indexed: 01/27/2023]
Abstract
Benzimidazoles, namely albendazole (ABZ) and mebendazole, are the only drugs licensed for the treatment of inoperable alveolar echinococcosis. In addition, amphotericin B (AMB) has shown effect against Echinococcus multilocularis as salvage treatment in humans. Both benzimidazoles and AMB are only parasitostatic against E. multilocularis and toxicity may limit long-term use. In the present study we examined the effect of combined treatment between ABZ and AMB on E. multilocularis larvae in an in vitro model. Vesicles were grown in a tissue culture model of metacestodes and hepatocytes. Drugs were added to the culture and the destructive effect on the vesicles was visually observed. Sequential application of ABZ and AMB yielded effective destruction of vesicles which was faster than the application of AMB alone. However, simultaneous application of ABZ and AMB had an inhibitory effect on vesicle destruction. After discontinuation of drug application, regrowth of vesicles occurred, hereby proving the parasitostatic effect of combined treatment against E. multilocularis larvae. Due to an inhibitory effect between ABZ and AMB against E. multilocularis larvae, we discourage from the simultaneous application of both drugs. If our in vitro results hold true in vivo, sequential application of ABZ and AMB would be an effective means for long-term suppression of larval growth. Long-term tolerance of both drugs could be improved by a reduction of side effects.
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18
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Echinococcus multilocularis: the impact of ionizing radiation on metacestodes. Exp Parasitol 2010; 127:127-34. [PMID: 20638383 DOI: 10.1016/j.exppara.2010.07.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2010] [Revised: 06/29/2010] [Accepted: 07/12/2010] [Indexed: 11/22/2022]
Abstract
Alveolar echinococcosis is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical options for the treatment of echinococcosis are not satisfactory, and novel drugs and/or other potential means of therapy are needed. E. multilocularis metacestodes are characterized by almost potentially unlimited growth, and also display other features of cancerous tumours. In this study, we exposed metacestodes that were generated in vitro to 50-100 Gy ionizing irradiation, and subsequently investigated the short-term (10-12 days post-treatment) and long-term (14 weeks post-treatment) effects. We found, that in the short-term, no release of alkaline phosphatase (EmAP) activity as a measure for potentially induced damage and loss of viability could be detected, and that the protein expression pattern and protease activities in vesicle fluids and medium supernatants did not alter dramatically following irradiation. However, irradiation was associated with distinct morphological and ultrastructural alterations in the tissue of metacestodes, affecting most notably cell-cell contacts, mitochondrial shape, glycogen-storage cells and lipid droplet formation. These could be detected already at 10 days following treatment and remained as such also in the long-term. In addition, as determined after 14 weeks of culture, irradiation affected the proliferation and the growth of E. multilocularis metacestodes. Thus, we demonstrate that radiotherapy does not have a clear-cut parasitocidal effect, but can lead to metabolic impairment of E. multilocularis metacestodes, as reflected by the distinct morphological and structural alterations induced by irradiation treatment.
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19
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Matt T, Akbergenov R, Shcherbakov D, Böttger EC. The Ribosomal A-site: Decoding, Drug Target, and Disease. Isr J Chem 2010. [DOI: 10.1002/ijch.201000003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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20
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Echinococcus multilocularis as an experimental model in stem cell research and molecular host-parasite interaction. Parasitology 2009; 137:537-55. [PMID: 19961652 DOI: 10.1017/s0031182009991727] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Totipotent somatic stem cells (neoblasts) are key players in the biology of flatworms and account for their amazing regenerative capability and developmental plasticity. During recent years, considerable progress has been made in elucidating molecular features of neoblasts from free-living flatworms, whereas their role in parasitic species has so far merely been addressed by descriptive studies. Very recently, however, significant advances have been made in the in vitro culture of neoblasts from the cestode Echinococcus multilocularis. The isolated cells proved capable of generating mature metacestode vesicles under laboratory conditions in a manner that closely resembles the oncosphere-metacestode transition during natural infections. Using the established neoblast cultivation protocols, combined with targeted manipulation of Echinococcus genes by RNA-interference, several fundamental questions of host-dependent parasite development can now be addressed. Here, I give an overview of current cultivation techniques for E. multilocularis neoblasts and present experimental approaches to study their function. Furthermore, I introduce the E. multilocularis genome sequencing project that is presently in an advanced stage. The combined input of data from the E. multilocularis sequencing project, stem cell cultivation, and recently initiated attempts to genetically manipulate Echinococcus will provide an ideal platform for hypothesis-driven research into cestode development in the next years.
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21
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Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes. Parasitology 2009; 137:569-87. [PMID: 19765346 DOI: 10.1017/s003118200999117x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Among the cestodes, Echinococcus granulosus, Echinococcus multilocularis and Taenia solium represent the most dangerous parasites. Their larval stages cause the diseases cystic echinococcosis (CE), alveolar echinococcosis (AE) and cysticercosis, respectively, which exhibit considerable medical and veterinary health concerns with a profound economic impact. Others caused by other cestodes, such as species of the genera Mesocestoides and Hymenolepis, are relatively rare in humans. In this review, we will focus on E. granulosus and E. multilocularis metacestode laboratory models and will review the use of these models in the search for novel drugs that could be employed for chemotherapeutic treatment of echinococcosis. Clearly, improved therapeutic drugs are needed for the treatment of AE and CE, and this can only be achieved through the development of medium-to-high throughput screening approaches. The most recent achievements in the in vitro culture and genetic manipulation of E. multilocularis cells and metacestodes, and the accessability of the E. multilocularis genome and EST sequence information, have rendered the E. multilocularis model uniquely suited for studies on drug-efficacy and drug target identification. This could lead to the development of novel compounds for the use in chemotherapy against echinococcosis, and possibly against diseases caused by other cestodes, and potentially also trematodes.
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22
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Abstract
Echinococcus granulosus and Echinococcus multilocularis are cestode parasites, of which the metacestode (larval) stages cause the neglected diseases cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. The benzimidazoles albendazole and mebendazole are presently used for the chemotherapeutical treatment, alone or prior to and after surgery. However, in AE these benzimidazoles do not appear to be parasiticidal in vivo. In addition, failures in drug treatments as well as the occurrence of side-effects have been reported, leading to discontinuation of treatment or to progressive disease. Therefore, new drugs are needed to cure AE and CE. Strategies that are currently employed in order to identify novel chemotherapeutical treatment options include in vitro and in vivo testing of broad-spectrum anti-infective drugs or drugs that interfere with unlimited proliferation of cancer cells. The fact that the genome of E. multilocularis has recently been sequenced has opened other avenues, such as the selection of novel drugs that interfere with the parasite signalling machinery, and the application of in silico approaches by employing the Echinococcus genome information to search for suitable targets for compounds of known mode of action.
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23
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Hobbie SN, Kalapala SK, Akshay S, Bruell C, Schmidt S, Dabow S, Vasella A, Sander P, Böttger EC. Engineering the rRNA decoding site of eukaryotic cytosolic ribosomes in bacteria. Nucleic Acids Res 2007; 35:6086-93. [PMID: 17766247 PMCID: PMC2094070 DOI: 10.1093/nar/gkm658] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Structural and genetic studies on prokaryotic ribosomes have provided important insights into fundamental aspects of protein synthesis and translational control and its interaction with ribosomal drugs. Comparable mechanistic studies in eukaryotes are mainly hampered by the absence of both high-resolution crystal structures and efficient genetic models. To study the interaction of aminoglycoside antibiotics with selected eukaryotic ribosomes, we replaced the bacterial drug binding site in 16S rRNA with its eukaryotic counterpart, resulting in bacterial hybrid ribosomes with a fully functional eukaryotic rRNA decoding site. Cell-free translation assays demonstrated that hybrid ribosomes carrying the rRNA decoding site of higher eukaryotes show pronounced resistance to aminoglycoside antibiotics, equivalent to that of rabbit reticulocyte ribosomes, while the decoding sites of parasitic protozoa show distinctive drug susceptibility. Our findings suggest that phylogenetically variable components of the ribosome, other than the rRNA-binding site, do not affect aminoglycoside susceptibility of the protein-synthesis machinery. The activities of the hybrid ribosomes indicate that helix 44 of the rRNA decoding site behaves as an autonomous domain, which can be exchanged between ribosomes of different phylogenetic domains for study of function.
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Affiliation(s)
- Sven N Hobbie
- Institut für Medizinische Mikrobiologie, Universität Zürich and Laboratorium für Organische Chemie, ETH Zürich, Switzerland.
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24
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Hemphill A, Spicher M, Stadelmann B, Mueller J, Naguleswaran A, Gottstein B, Walker M. Innovative chemotherapeutical treatment options for alveolar and cystic echinococcosis. Parasitology 2007; 134:1657-70. [PMID: 17631693 DOI: 10.1017/s0031182007003198] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Echinococcus granulosus and Echinococcus multilocularis are cestode parasites, of which the metacestode (larval) stages cause the diseases cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. Albendazole and mebendazole are presently used for chemotherapeutical treatment. However, these benzimidazoles do not appear to be parasiticidal in vivo against AE. In addition, failures in drug treatments as well as the occurrence of side-effects have been reported. New drugs are needed to cure AE and CE, which are considered to be neglected diseases. Strategies currently being implemented to identify novel chemotherapeutical treatment options include (i) conventional primary in vitro testing of broad-spectrum anti-infective drugs, either in parallel with, or followed by, animal experimentation; (ii) studies of drugs which interfere with the proliferation of cancer cells and of Echinococcus metacestodes; (iii) exploitation of the similarities between the parasite and mammalian signalling machineries, with a special focus on targeting specific signalling receptors; (iv) in silico approaches, employing the current Echinococcus genomic database information to search for suitable targets for compounds with known modes of action. In the present article, we review the efforts toward obtaining better anti-parasitic compounds which have been undertaken to improve chemotherapeutical treatment of echinococcosis, and summarize the achievements in the field of host-parasite interactions which may also lead to new immuno-therapeutical options.
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Affiliation(s)
- A Hemphill
- Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
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25
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Reuter S, Manfras B, Merkle M, Härter G, Kern P. In vitro activities of itraconazole, methiazole, and nitazoxanide versus Echinococcus multilocularis larvae. Antimicrob Agents Chemother 2006; 50:2966-70. [PMID: 16940089 PMCID: PMC1563547 DOI: 10.1128/aac.00476-06] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Albendazole (ABZ) and mebendazole are the only drugs licensed for treatment of human alveolar echinococcosis. In order to augment the armamentarium against this deadly disease, we tested a series of drugs for their efficacy against Echinococcus multilocularis larvae. E. multilocularis larvae grown intraperitoneally in Mongolian gerbils were transferred into tissue culture. Vesicles budded from the tissue blocks and after 6 weeks, drugs were added, and the effect on the vesicles was observed. We tested the following drugs at various concentrations: ABZ, artemether, caspofungin, itraconazole (ITZ), ivermectin, methiazole (MTZ), miltefosine, nitazoxanide (NTZ), rifampin, and trimethoprim-sulfamethoxazole. ABZ, ITZ, MTZ, and NTZ effectively destroyed parasite vesicles in this in vitro culture system. At high NTZ doses of 10 microg/ml, disintegration of all vesicles was observed after 7 days and was significantly more rapid than with ABZ at equal concentrations (21 days). After drug discontinuation, regrowth of vesicles occurred between 7 and 14 days for all four drugs, indicating a parasitostatic effect. Combination treatment with NTZ-ABZ at concentrations between 1 and 10 microg/ml for either 3 weeks, 3 months, or 6 months yielded no vesicle regrowth during 8 months after drug discontinuation. The treated larval tissue was injected intraperitoneally into gerbils, and no regrowth of larval tissue was observed, suggesting a parasitocidal effect after combined treatment. ITZ, MTZ, and NTZ are potent inhibitors of larval growth, although they proved to be parasitostatic only. The combination of NTZ plus ABZ was parasitocidal in vitro. Animal experiments are warranted for studies of dose, toxicity, and drug interactions.
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Affiliation(s)
- Stefan Reuter
- Section of Infectious Diseases and Clinical Immunology, University Hospital of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany.
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