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Sent on Thursday, 2011 Jun 02Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | PLoS Negl Trop Dis. 2011 May;5(5):e1161. Epub 2011 May 24.Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma.Hobbie SN, Kaiser M, Schmidt S, Shcherbakov D, Janusic T, Brun R, Böttger EC.SourceInstitute of Medical Microbiology, University of Zurich, Zurich, Switzerland. AbstractAminoglycoside 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function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences.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. |
| 2. | PLoS Negl Trop Dis. 2011 May;5(5):e1164. Epub 2011 May 24.Crystal Structures of T. b. rhodesiense Adenosine Kinase Complexed with Inhibitor and Activator: Implications for Catalysis and Hyperactivation.Kuettel S, Greenwald J, Kostrewa D, Ahmed S, Scapozza L, Perozzo R.SourcePharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Lausanne, Switzerland. AbstractBACKGROUND:The essential purine salvage pathway of Trypanosoma brucei bears interesting catalytic enzymes for chemotherapeutic intervention of Human African Trypanosomiasis. Unlike mammalian cells, trypanosomes lack de novo purine synthesis and completely rely on salvage from their hosts. One of the key enzymes is adenosine kinase which catalyzes the phosphorylation of ingested adenosine to form adenosine monophosphate (AMP) utilizing adenosine triphosphate (ATP) as the preferred phosphoryl donor. METHODS AND FINDINGS:Here, we present the first structures of Trypanosoma brucei rhodesiense adenosine kinase (TbrAK): the structure of TbrAK in complex with the bisubstrate inhibitor P(1),P(5)-di(adenosine-5')-pentaphosphate (AP5A) at 1.55 Å, and TbrAK complexed with the recently discovered activator 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine (compound 1) at 2.8 Å resolution. CONCLUSIONS:The structural details and their comparison give new insights into substrate and activator binding to TbrAK at the molecular level. Further structure-activity relationship analyses of a series of derivatives of compound 1 support the observed binding mode of the activator and provide a possible mechanism of action with respect to their activating effect towards TbrAK. |
| 3. | PLoS Negl Trop Dis. 2011 May;5(5):e1167. Epub 2011 May 24.Gene Expression Profiling and Molecular Characterization of Antimony Resistance in Leishmania amazonensis.do Monte-Neto RL, Coelho AC, Raymond F, Légaré D, Corbeil J, Melo MN, Frézard F, Ouellette M.SourceDepartamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil. AbstractBACKGROUND:Drug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we investigate molecular alterations in antimony resistance in the New World species L. amazonensis. METHODS/PRINCIPAL FINDINGS:We selected populations of L. amazonensis promastigotes for resistance to antimony by step-wise drug pressure. Gene expression of highly resistant mutants was studied using DNA microarrays. RNA expression profiling of antimony-resistant L. amazonensis revealed the overexpression of genes involved in drug resistance including the ABC transporter MRPA and several genes related to thiol metabolism. The MRPA overexpression was validated by quantitative real-time RT-PCR and further analysis revealed that this increased expression was correlated to gene amplification as part of extrachromosomal linear amplicons in some mutants and as part of supernumerary chromosomes in other mutants. The expression of several other genes encoding hypothetical proteins but also nucleobase and glucose transporter encoding genes were found to be modulated. CONCLUSIONS/SIGNIFICANCE:Mechanisms classically found in Old World antimony resistant Leishmania were also highlighted in New World antimony-resistant L. amazonensis. These studies were useful to the identification of resistance molecular markers. |
| 4. | Can J Infect Dis Med Microbiol. 2010 Summer;21(2):e79-83.Systemic therapy of New World cutaneous leishmaniasis: A case report and review article.Abadir A, Patel A, Haider S.SourceDepartment of Medicine; AbstractCutaneous leishmaniasis is a disease endemic to Central and South America, Mexico and the Caribbean, and affects millions of people. As travel to these regions becomes more common, cutaneous leishmaniasis is becoming a disease of increasing importance in the developed world. However, disease recognition and access to appropriate therapy for cutaneous leishmaniasis remains a challenge in North America. The present article reports a case of cutaneous leishmaniasis in a Canadian man following a trip to Costa Rica. Species-specific diagnosis was confirmed by polymerase chain reaction analysis of a skin biopsy, which was positive for Leishmania panamensis. After failing a course of itraconazole, the patient was successfully treated with sodium stibogluconate, despite significant barriers to administering this therapy, and the paucity of data regarding its efficacy and tolerability. The pathophysiology, diagnosis and systemic treatment of cutaneous leishmaniasis, as well as its emerging presence in the developed world, are reviewed. |
| 5. | Open Med Chem J. 2011;5:31-9. Epub 2011 Mar 9.Structures, targets and recent approaches in anti-leishmanial drug discovery and development.Seifert K.SourceLondon School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. AbstractRecent years have seen a significant improvement in available treatment options for leishmaniasis. Two new drugs, miltefosine and paromomycin, have been registered for the treatment of visceral leishmaniasis (VL) in India since 2002. Combination therapy is now explored in clinical trials as a new treatment approach for VL to reduce the length of treatment and potentially prevent selection of resistant parasites. However there is still a need for new drugs due to safety, resistance, stability and cost issues with existing therapies. The search for topical treatments for cutaneous leishmaniasis (CL) is ongoing. This review gives a brief overview of recent developments and approaches in anti-leishmanial drug discovery and development. |
| 6. | Open Med Chem J. 2011;5:4-10. Epub 2011 Mar 9.Current developments in the therapy of protozoan infections.Zucca M, Savoia D.SourceDepartment of Clinical and Biological Sciences, University of Torino, Italy. AbstractProtozoan parasites cause serious human and zoonotic infections, including life-threatening diseases such as malaria, African and American trypanosomiasis, and leishmaniasis. These diseases are no more common in the developed world, but together they still threaten about 40% of the world population (WHO estimates). Mortality and morbidity are high in developing countries, and the lack of vaccines makes chemotherapy the only suitable option. However, available antiparasitic drugs are hampered by more or less marked toxic side effects and by the emergence of drug resistance. As the main prevalence of parasitic diseases occurs in the poorest areas of the world, the interest of the pharmaceutical companies in the development of new drugs has been traditionally scarce. The establishment of public-private partnerships focused on tropical diseases is changing this situation, allowing the exploitation of the technological advances that took place during the past decade related to genomics, proteomics, and in silico drug discovery approaches. These techniques allowed the identification of new molecular targets that in some cases are shared by different parasites. In this review we outline the recent developments in the fields of protease and topoisomerase inhibitors, antimicrobial and cell-penetrating peptides, and RNA interference. We also report on the rapidly developing field of new vectors (micro and nano particles, mesoporous materials) that in some cases can cross host or parasite natural barriers and, by selectively delivering new or already in use drugs to the target site, minimize dosage and side effects. |
| 7. | J Infect Dis. 2011 Jul;204(1):36-43.Endogenous IL-13 Plays a Crucial Role in Liver Granuloma Maturation During Leishmania donovani Infection, Independent of IL-4R{alpha}-Responsive Macrophages and Neutrophils.McFarlane E, Carter KC, McKenzie AN, Kaye PM, Brombacher F, Alexander J.SourceStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow. AbstractPrevious studies comparing interleukin 4 receptor α (IL-4Rα)(-/-) and interleukin 4 (IL-4)(-/-) BALB/c mice have indicated that interleukin 13 (IL-13), whose receptor shares the IL-4Rα subunit with IL-4, plays a protective role during visceral leishmaniasis. We demonstrate that IL-13(-/-) BALB/c mice were less able to control hepatic growth of Leishmania donovani compared with wild-type mice. This correlated with significantly retarded granuloma maturation in IL-13(-/-) mice, defective interferon γ (IFN-γ) production, and elevated IL-4 and interleukin 10 (IL-10) levels. L. donovani-infected IL-13(-/-) mice also responded poorly to sodium stibogluconate-mediated chemotherapy compared with wild-type BALB/c mice. Because murine lymphocytes do not have IL-13 receptors, we examined the ability of macrophage/neutrophil-specific IL-4Rα(-/-) mice to control primary infection with L. donovani and to respond to chemotherapy. Macrophage/neutrophil-specific IL-4Rα(-/-) mice were as resistant to leishmaniasis as wild-type mice, and chemotherapy retained its efficacy. Consequently, in L. donovani infected BALB/c mice, IL-13 promotes hepatic granuloma formation and controls parasite burdens independently of direct effects on macrophages/neutrophils. |
| 8. | Mayo Clin Proc. 2011 Jun;86(6):561-83.Antiparasitic therapy.Kappagoda S, Singh U, Blackburn BG.SourceStanford University School of Medicine, Division of Infectious Diseases and Geographic Medicine, 300 Pasteur Dr, Grant Bldg, Room S-101, Stanford, CA 94305-5107. blackburn@stanford.edu. AbstractParasitic diseases affect more than 2 billion people globally and cause substantial morbidity and mortality, particularly among the world's poorest people. This overview focuses on the treatment of the major protozoan and helminth infections in humans. Recent developments in antiparasitic therapy include the expansion of artemisinin-based therapies for malaria, new drugs for soil-transmitted helminths and intestinal protozoa, expansion of the indications for antiparasitic drug treatment in patients with Chagas disease, and the use of combination therapy for leishmaniasis and human African trypanosomiasis. |
| 9. | Exp Parasitol. 2011 May 24. [Epub ahead of print]Energetic metabolism of axenic progmastigotes of Leishmania (Viannia) braziliensis.Costa TL, Ribeiro-Dias F, Oliveira MA, Bezerra JC, Vinaud MC.SourceLaboratory of Host Parasite Relationship Studies/IPTSP/UFG - Rua 235, s/n, Setor Leste Universitário, Goiânia, Goiás, CEP: 74650-050, Brazil. AbstractLeishmania spp are protozoans capable of carbohydrates degradation and as energy source they can use glucose, aminoacids or lipids from the environment. The products of the metabolic pathways such as organic acids may be used as an index of their energetic metabolic profile. Therefore, in this study a metabolic profile comparison was made between promastigotes from one reference strain (MHOM/BR/1975/M2903) and two different isolates of Leishmania (Viannia) braziliensis (MHOM/BR/2003/IMG3 and MHOM/BR/2005/RPL5). The parasites culture was performed in complete Grace's culture media seeded in 24-well plates at 26°C. During the growth curve performance samples were collected from the logarithmic and stationary phases of culture and therefore analyzed by high performance liquid chromatography (HPLC) and spectrophotometry assays to determine the concentrations of glucose, lactate, citrate, α-ketoglutarate, succinate, fumarate, malate, oxaloacetate and β-hydroxybutirate which are indicative of the energetic pathways. It was possible to detect an increase in the glucose from the stationary phase from the M2903 strain when compared to the logarithmic phase while in the IMG3 and RPL5 isolates there was a decrease (p<0.05). The spectrophotometric and chromatographic results indicated that the logarithmic phase which presents higher energy consumption due to the intense replication rate have the energetic pathways intensified. It was also possible to note some metabolic differences between the analyzed parasites which may indicate possible adaptations of the parasite when facing different environmental and physiological conditions during its life cycle and that these differences may help in the understanding of the diversity of the host-parasite relationship from Leishmania parasites. Copyright © 2011. Published by Elsevier Inc. |
| 10. | J Biomed Nanotechnol. 2011 Feb;7(1):50-1.Design and development of Amphotericin B bearing polycaprolactone microparticles for macrophage targeting.Singh P, Gupta A, Jaiswal A, Dube A, Mishra S, Chaurasia MK.SourcePharmaceutics Division, Central Drug Research Institute, (Council of Scientific and Industrial Research, India), P.O. Box 173, M. G. Marg, Lucknow 226001, India. AbstractAntileishmanial efficacy of Amphotericin B bearing polycaprolactone (PCL) microparticles was investigated. The microparticles were prepared, optimized and subjected to in vitro characterization for shape (spherically structured), particle size (9.83 +/- 1.12 microm), entrapment efficiency (43.54 +/- 3.98%) and in vitro drug release. The study revealed that PCL microparticles bearing Amphotericin B can be effectively used to target leishmanial parasites residing in macrophages. |
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