Cruzi Agents Research Articles

Facing diseases caused by trypanosomatid parasites: rational design of multifunctional oxidovanadium(IV) complexes with bioactive ligands

Searching for new prospective drugs against Chagas disease (American trypanosomiasis) and Leishmaniasis, a series of five heteroleptic vanadium compounds, [VIVO(L-H)(mpo)], where L are 8-hydroxyquinoline derivatives and mpo is 2-mercaptopyridine N-oxide, are synthesized and characterized. Comprehensive characterizations are conducted in solid state and in solution. The compounds are evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi and in promastigotes of Leishmania infantum, alongside on VERO cells, as a mammalian cell model. The compounds exhibit activity against both forms of T. cruzi and promastigotes of L. infantum, with the trypomastigote infective stage of T. cruzi displaying the highest sensitivity. The most selective vanadium compound [VIVO(L2-H)(mpo)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, globally shows adequate selectivity towards the parasite and was selected to carry out further in-depth biological studies. [VIVO(L2-H)(mpo)] significantly impacted the infection potential of cell-derived trypomastigotes and hindered the replication of the T. cruzi amastigote form. Low total vanadium uptake by T. cruzi parasites and preferential accumulation in the soluble proteins fraction, with negligible localization in the DNA fraction, are determined. A trypanocide effect is observed across various concentrations of the compound. The generation of oxidative stress and the induction of mitochondria-dependent apoptosis are proposed as the main mechanisms of the parasite’s death by the VIVO compounds. Both theoretical predictions and experimental data support the hypothesis that inhibiting the parasite-specific enzyme NADH-fumarate reductase activity plays a crucial role in the trypanocidal action of these complexes. Globally, [VIVO(L-H)(mpo)] complexes could be considered interesting anti-T. cruzi agents that deserve further research.

Ligand-Based Virtual Screening and Molecular Docking of Benzimidazoles as Potential Inhibitors of Triosephosphate Isomerase Identified New Trypanocidal Agents.

Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of T. cruzi TIM (TcTIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC50) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TcTIM. Additionally, BP5 showed a low docking score (−5.9 Kcal/mol) on human TIM compared to the control ligand (−7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.

Synthesis and biological evaluation in vitro and in silico of N-propionyl-N'-benzeneacylhydrazone derivatives as cruzain inhibitors of Trypanosoma cruzi.

An N-acylhydrazone scaffold has been used to develop new drugs with diverse biological activities, including trypanocidal activity against different strains of Trypanosoma cruzi. However, their mechanism of action is not clear, although in T. cruzi it has been suggested that the enzyme cruzain is involved. The aim in this work was to obtain new N-propionyl-N'-benzeneacylhydrazone derivatives as potential anti-T. cruzi agents and elucidate their potential mechanism of action by a molecular docking analysis and effects on the expression of the cruzain gene. Compounds 9 and 12 were the most active agents against epimastigotes and compound 5 showed better activity than benznidazole in T. cruzi blood trypomastigotes. Additionally, compounds 9 and 12 significantly increase the expression of the cruzain gene. In summary, the in silico and in vitro data presented herein suggest that compound 9 is a cruzain inhibitor.

New aryloxy-quinone derivatives with promising activity on Trypanosoma cruzi.

Continuing with a program to develop new quinone derivatives as biologically active compounds, we designed and synthesized a new series of aryloxy-quinones, which were evaluated in vitro against Trypanosoma cruzi in epimastigote form. Chemical modifications in three specific moieties on the aryloxy-quinone core were considered for developing new anti-T. cruzi agents. The majority of our new quinones showed higher potency (IC50 values of <0.70 µM) than nifurtimox, a known pharmaceutical used as a baseline drug (IC50 values of 7.00 µM); however, only two of them elicited higher selectivity than nifurtimox against Vero cells. A structure-activity relationship analysis provided information about the stereoelectronic features of these compounds, which are responsible for an increase in trypanosomicidal activity. Using a pharmacophore model, we mapped the substitution patterns of the five pharmacophoric features of trypanosomicidal activity. We chose the Epc1 compounds and found no relationship with the trypanosomicidal effects. These results provided useful information about the structural characteristics for developing new aryloxy-quinones with higher potency against the protozoan parasite T. cruzi.

New heteroleptic oxidovanadium(V) complexes: synthesis, characterization and biological evaluation as potential agents against Trypanosoma cruzi.

Searching for prospective vanadium-based agents against Trypanosoma cruzi, the parasite causing Chagas disease, four new [VVO(8HQ-H)(L-2H)] compounds, where 8HQ is 8-hydroxyquinoline and L are tridentate salicylaldehyde semicarbazone derivatives L1-L4, were synthesized and characterized in the solid state and in solution. The compounds were evaluated on T. cruzi epimastigotes (CL Brener) as well as on VERO cells, as mammalian cell model. Compounds showed activity against T. cruzi (IC50 6.2-10.5μM) of the same order than Nifurtimox and 8HQ, and a four- to sevenfold activity increase with respect to the free semicarbazones. For comparison, [VVO2(L-H)] series was prepared and the new [VVO2(L3-H)] was fully characterized. They showed negligible activity and low selectivity towards the parasite. The inclusion of 8HQ as ligand in [VVO(8HQ-H)(L-2H)] compounds led to good activities and increased selectivity towards the parasite with respect to 8HQ. 51V NMR experiments, performed to get insight into the nature of the active species, suggested partial decomposition of the compounds in solution to [VVO2(L-H)] and 8HQ. Depending on the dose, the compounds act as trypanocide or trypanostatic. A high uptake of vanadium in the parasites (58.51-88.9% depending on dose) and a preferential accumulation in the soluble protein fraction of the parasite was determined. Treated parasites do not seem to show a late apoptotic/necrotic phenotype suggesting a different cell death mechanism. In vivo toxicity study on zebrafish model showed no toxicity up to a 25µM concentration of [VVO(8HQ-H)(L1-2H)]. These compounds could be considered prospective anti-T. cruzi agents that deserve further research.

Therapeutic activity of organotin compounds against Trypanosoma cruzi

An estimated 8 million people in Mexico, Central America, and South America are infected with Chagas disease (ChD) caused by the protozoan parasite Trypansoma cruzi (T. cruzi). ChD is a zoonotic disease transmitted to humans and animals by the insect vector Triatomine, also known as “kissing bug”. About 20 to 30% of infected people will develop symptomatic, potentially life‐threatening ChD. T. cruzi is carried in the hindgut of the triatomine bugs and transmission occurs when infected bug feces contact mucosal membranes or open wounds. Humans can also be infected through vector‐borne, blood‐borne, organ derived, congenital and oral transmission routes. Currently, ChD can be treated with Benznidazole and Nifurtiox. However, its efficacy is limited. In addition, the undesirable side effects of both drugs are a major drawback. Thus, the development of effective new chemotherapies against ChD is imperative. Previously, organotin compounds have shown to be broad and potent biocides against eukaryotic infections ranging from fungicides to acaricides. However, the use of these compounds against parasitic infections has not been investigated, possibly due to their immunotoxicity. Therefore, the aim of this study is to assess novel organotin compounds as anti‐Trypanosoma cruzi agents in an in vitro model of ChD. In this study, we tested the activity of a tetravalent organotin compound [MeS(CH2)3]2SnCl2 and compared it to commercially available organotin compounds such as Ph2SnCl2, (butyl)2SnCl2, and (octyl)2SnCl2. [MeS(CH2)3]2SnCl2. It is important to highlight that our novel compound acts as a benign organotin compound in respect to interactions with human natural killer cells. Therefore, we used the epimastigote forms of the transgenic strain of T. cruzi CL‐Brener expressing luciferase to test for parasitic viability; 2 × 106 parasites were incubated with the compounds in a range of 2 ‐ 0.625 mM for 72 hours at 28°C. Two controls were included in the assay, a negative control using only the drug diluent (1% DMSO) and a positive control where the parasites were treated with Benznidazole (80 mM). Following incubation, parasite viability was measured by the presence of luminescence after the addition of the luciferin substrate by ONE‐Gloä Luciferase Assay System (Promega). Treatment with compounds Ph2SnCl2 and (butyl)2SnCl2 resulted in an IC50 of 0.3 and 0.125 mM. Together, these preliminary results provide evidence that compounds Ph2SnCl2 and (butyl)2SnCl2 affect parasite viability. Thus, these findings can be further extended to investigate the tetravalent organotin compound [MeS(CH2)3]2SnCl2 therapeutic effects in the infective and intracellular stages of T. cruzi, and its potential cell cytotoxicity in human cells.Support or Funding InformationResearch reported in this poster was supported by the National Institute of General Medical Sciences of the National Institutes of Health under linked Award Numbers RL5GM118969, TL4GM118971, and UL1GM118970. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Shedding light on lipid metabolism in Kinetoplastida: A phylogenetic analysis of phospholipase D protein homologs

Unicellular flagellates that make up the class Kinetoplastida include multiple parasites responsible for public health concerns, including Trypanosoma brucei and T. cruzi (agents of African sleeping sickness and Chagas disease, respectively), and various Leishmania species, which cause leishmaniasis. These diseases are generally difficult to eradicate, with treatments often having lethal side effects and/or being effective only during the acute phase of the diseases, when most patients are still asymptomatic. Phospholipid signaling and metabolism are important in the different life stages of Trypanosoma, including playing a role in transitions between stages and in immune system evasion, thus, making the responsible enzymes into potential therapeutic targets. However, relatively little is understood about how the pathways function in these pathogens. Thus, in this study we examined evolutionary history of proteins from one such signaling pathway, namely phospholipase D (PLD) homologs. PLD is an enzyme responsible for synthesizing phosphatidic acid (PA) from membrane phospholipids. PA is not only utilized for phospholipid synthesis, but is also involved in many other signaling pathways, including biotic and abiotic stress response. 37 different representative Kinetoplastida genomes were used for an exhaustive search to identify putative PLD homologs. The genome of Bodo saltans was the only one of surveyed Kinetoplastida genomes that encoded a protein that clustered with plant PLDs. The representatives from other Kinetoplastida species clustered together in two different clades, thought to be homologous to the PLD superfamily, but with shared sequence similarity with cardiolipin synthases (CLS), and phosphatidylserine synthases (PSS). The protein structure predictions showed that most Kinetoplastida sequences resemble CLS and PSS, with the exception of 5 sequences from Bodo saltans that shared significant structural similarities with the PLD sequences, suggesting the loss of PLD-like sequences during the evolution of parasitism in kinetoplastids. On the other hand, diacylglycerol kinase (DGK) homologs were identified for all species examined in this study, indicating that DGK could be the only pathway for the synthesis of PA involved in lipid signaling in these organisms due to genome streamlining during transition to parasitic lifestyle. Our findings offer insights for development of potential therapeutic and/or intervention approaches, particularly those focused on using PA, PLD and/or DGK related pathways, against trypanosomiasis, leishmaniasis, and Chagas disease.

Nanoemulsions of sulfonamide carbonic anhydrase inhibitors strongly inhibit the growth of Trypanosoma cruzi

Sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors targeting the α-class enzyme from the protozoan pathogen Trypanosoma cruzi, responsible of Chagas disease, were recently reported. Although many such derivatives showed low nanomolar activity in vitro, they were inefficient anti-T. cruzi agents in vivo. Here, we show that by formulating such sulfonamides as nanoemulsions in clove (Eugenia caryophyllus) oil, highly efficient anti-protozoan effects are observed against two different strains of T. cruzi. These effects are probably due to an enhanced permeation of the enzyme inhibitor through the nanoemulsion formulation, interfering in this way with the life cycle of the pathogen either by inhibiting pH regulation or carboxylating reactions in which bicarbonate/CO2 are involved. This type of formulation of sulfonamides with T. cruzi CA inhibitory effects may lead to novel therapeutic approaches against this orphan disease.

Identification of New Anti-Trypanosoma Cruzi Agents in Some Uruguayan Plants by NMR-Based Metabolomic Profiling

Identification of New Anti-Trypanosoma Cruzi Agents in Some Uruguayan Plants by NMR-Based Metabolomic Profiling

Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi.

BackgroundTrypanosoma cruzi causes Chagas disease, an endemic and debilitating illness in Latin America. Lately, owing to extensive population movements, this neglected tropical disease has become a global health concern. The two clinically available drugs for the chemotherapy of Chagas disease have rather high toxicity and limited efficacy in the chronic phase of the disease, and may induce parasite resistance. The development of new anti-T. cruzi agents is therefore imperative. The enzyme N-myristoyltransferase (NMT) has recently been biochemically characterized, shown to be essential in Leishmania major, Trypanosoma brucei, and T. cruzi¸ and proposed as promising chemotherapeutic target in these trypanosomatids.Methodology/Principal FindingsHere, using high-content imaging we assayed eight known trypanosomatid NMT inhibitors, against mammal-dwelling intracellular amastigote and trypomastigote stages and demonstrated that three of them (compounds 1, 5, and 8) have potent anti-proliferative effect at submicromolar concentrations against T. cruzi, with very low toxicity against human epithelial cells. Moreover, metabolic labeling using myristic acid, azide showed a considerable decrease in the myristoylation of proteins in parasites treated with NMT inhibitors, providing evidence of the on-target activity of the inhibitors.Conclusions/SignificanceTaken together, our data point out to the potential use of NMT inhibitors as anti-T. cruzi chemotherapy.

ChemInform Abstract: 2‐Pyridyl Thiazoles as Novel anti‐Trypanosoma cruzi Agents: Structural Design, Synthesis and Pharmacological Evaluation.

AbstractThe majority of new compounds (III) and (V) are potent cruzain inhibitors and show similar or greater trypanocidal efficacy than standard drug benznidazole, used for treatment of Chagas disease.

Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death

Chagas disease, caused by Trypanosoma cruzi, is a life-threatening infection leading to approximately 12,000 deaths per year. T. cruzi is susceptible to thiosemicarbazones, making this class of compounds appealing for drug development. Previously, the homologation of aryl thiosemicarbazones resulted in an increase in anti-T. cruzi activity in comparison to aryl thiosemicarbazones without a spacer group. Here, we report the structural planning, synthesis and anti-T. cruzi evaluation of new aryl thiosemicarbazones (9a–x), designed as more conformationally restricted compounds. By varying substituents attached to the phenyl ring, substituents were observed to retain, enhance or greatly increase the anti-T. cruzi activity, in comparison to the nonsubstituted derivative. In most cases, hydrophobic and bulky substituents, such as bromo, biphenyl and phenoxyl groups, greatly increased antiparasitic activity. Specifically, thiosemicarbazones were identified that inhibit the epimastigote proliferation and were toxic for trypomastigotes without affecting mouse splenocytes viability. The most potent anti-T. cruzi thiosemicarbazones were evaluated against cruzain. However, inhibition of this enzyme was not observed, suggesting that the compounds work through another mechanism. In addition, examination of T. cruzi cell death showed that these thiosemicarbazones induce apoptosis. In conclusion, the structural design executed within the series of aryl thiosemicarbazones (9a–x) led to the identification of new potent anti-T. cruzi agents, such as compounds (9h) and (9r), which greatly inhibited epimastigote proliferation, and demonstrated a toxicity for trypomastigotes, but not for splenocytes. Mechanistically, these compounds do not inhibit the cruzain, but induce T. cruzi cell death by an apoptotic process.

Searching for Vanadium‐Based Prospective Agents against Trypanosoma cruzi: Oxidovanadium(IV) Compounds with Phenanthroline Derivatives as Ligands

AbstractSearching for new promising metal‐based drugs for the treatment of parasitic diseases against Trypanosoma cruzi, three related oxidovanadium(IV) complexes, [VIVO(SO4)(H2O)2(NN)], with the phenanthroline derivatives (NN) 1,2,5thiadiazolo[3,4‐f]1,10phenanthroline (tdzp), 1,10‐phenanthroline‐5, 6‐dione (phendione), and 5,6‐epoxy‐5,6‐dihydro‐1,10‐phenanthroline (epoxyphen) are synthesized, characterized, and evaluated in vitro as anti‐T. cruzi agents. The compounds are characterized in the solid state and in solution by elemental analysis, electrospray ionization mass spectrometry (ESI‐MS), conductimetric measurements, and infrared (FTIR), UV/Vis, and electronic paramagnetic resonance (EPR) spectroscopy. EPR spectroscopy suggests that the ligands act as bidentate, binding through both nitrogen donor atoms in an axial‐equatorial mode. DFT calculations corroborate the structural assignments. The stability of the complexes in solution is evaluated by EPR and 51V‐ NMR spectroscopy and all complexes show reasonable stability. The anti‐T. cruzi activity of the complexes was tested by measuring the growth inhibitory effect on the epimastigote life cycle form of the parasite (Dm28c strain). All complexes show IC50 values in the micromolar range against T. cruzi and display activities of the same order of that of Nifurtimox, but lower than that of the previously reported analogue [VIVO(SO4)(H2O)2(dppz)] (dppz = dipyrido[3, 2‐a:2′,3′‐c]phenazine). Furthermore, DNA was evaluated as a potential target by using atomic force microscopy (AFM), showing that the complexes display ability to interact with this biomolecule.

ChemInform Abstract: Synthesis and Biological Evaluation of Some Novel 1‐Indanone Thiazolylhydrazone Derivatives as anti‐Trypanosoma cruzi Agents.

AbstractMost of the newly synthesized title compounds (III) show promising activity against epimastigotes, tryptomastigotes and amastigote forms.

Synthesis and Biological Evaluation of New Sulfonamide Derivatives as Potential Anti-Trypanosoma cruzi Agents

Synthesis and Biological Evaluation of New Sulfonamide Derivatives as Potential Anti-Trypanosoma cruzi Agents

New imidazolidine derivatives as anti-Trypanosoma cruzi agents: structure–activity relationships

Imidazolidine derivatives are key components for the development of bioactive compounds for the treatment of many diseases, especially Chagas. In fact, others studies showed that the imidazolidine-2,4-dione has stood out by presenting a wide spectrum of pharmacological activities including anticonvulsants, antiarrhythmic, and antiparasitic. In the present study, we investigated the morphological alterations induced by imidazolidine derivates LPSF/NN-52 and LPSF/NN-100 on trypomastigotes forms of Trypanosoma cruzi through ultrastructural analysis by electron microscopy. Many concentrations were used to measure the antiparasitic propriety promoted by imidazolidine derivatives, and our study indicates that parasites treated with 13 μg mL(-1) of the imidazolidine derivates for 24 h revealed severe damage to the parasite's mitochondrial complex. Beyond that, also observed in treated parasites were the following: myelin bodies, enlargement of cytoplasm vacuole, fragmentation of endoplasmic reticulum, and some treated samples clearly showed signs of necrosis. To confirm the ultrastructural results, some assays were performed for knowledge cellular death induction promoted by imidazolidine derivates against immune spleen cells. The induction of the necrotic process through derivatives LPSF/NN-52 and LPSF/NN-100 showed similar results in relation to nifurtimox and benznidazole. In the last assays, it was demonstrated that NN-100 was efficient against epimastigotes and trypomastigotes forms and these results reinforce the mechanisms of action of both new imidazolidine derivatives against T. cruzi.

Synthesis and Biological Evaluation of New Sulfonamide Derivatives as Potential Anti-Trypanosoma cruzi Agents

Chagas disease continues to be one of the main parasitic diseases in Latin America. Despite the fact that it was discovered more than 100 years ago, no suitable pharmacologic treatment is available. We report the synthesis of new sulfonamidoquinoline and sulfonamides derivatives that were evaluated in vitro against two strains of Trypanosoma cruzi (NINOA and INC-5). Structure-activity relationship analysis indicated that small aromatic and large aromatic substituents on 4-aminoquinaldine increased trypanocidal activity on INC-5 and NINOA strains, respectively. Additionally, results show the importance of the sulfonamide group as a scaffold for the development of new anti-T. cruzi agents. Seven sulfonamide derivatives showed better lytic activity than nifurtimox and beznidazole against both strains of T. cruzi. N- (biphenyl-4-yl-sulfonyl)-nicotinamide (P-012) was established as the leader of the series for the development of more effective agents.

Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones.

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC₅₀ to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC₅₀ of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.

Chagas disease research: Advances and needs

American trypanosomiasis – a zoonotic disease caused by Trypanosoma cruzi (Protozoa, Kinetoplastida) – is transmitted to humans by blood-sucking triatomine bugs, blood transfusion and congenital transmission. Successful regional vector control programs based on the residual application of insecticide and improved screening of blood donors have achieved important reductions in the incidence of Chagas disease in many Latin American countries. However, this approach has been ineffective in some geographic areas such as the Gran Chaco. As a result, the development of effective new tools in these areas to prevent house reinfestation by triatomine bugs is a high research priority. No less important is the need of innovative approaches including those generated from genomics to improve upon existing diagnostic tests and to develop new parasitological tests for the early diagnosis of congenital infection in the newborn and in immunocompromised patients, as well as for the assessment of treatment response (PCR; antigenemia, recombinant antigens,synthetic peptides etc.). There is also a pressing need of developing new anti-T. cruzi agents with high activity in both the acute and chronic phases, and epidemiological methods that me may be used to estimate the prevalence of infection, subclinical disease and treatment needs in endemic and non-endemic countries. Abstracts for SupplementInternational Journal of Infectious DiseasesVol. 14Preview Full-Text PDF Open Archive