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2.
PLoS Negl Trop Dis ; 14(7): e0008439, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628683

RESUMO

Leishmaniasis constitutes the 9th largest disease burden among all infectious diseases. Control of this disease is based on a short list of chemotherapeutic agents headed by pentavalent antimonials, followed by miltefosine and amphotericin B; drugs that are far from ideal due to host toxicity, elevated cost, limited access, and high rates of drug resistance. Knowing that the composition of extracellular vesicles (EVs) can vary according to the state of their parental cell, we hypothesized that EVs released by drug-resistant Leishmania infantum parasites could contain unique and differently enriched proteins depending on the drug-resistance mechanisms involved in the survival of their parental cell line. To assess this possibility, we studied EV production, size, morphology, and protein content of three well-characterized drug-resistant L. infantum cell lines and a wild-type strain. Our results are the first to demonstrate that drug-resistance mechanisms can induce changes in the morphology, size, and distribution of L. infantum EVs. In addition, we identified L. infantum's core EV proteome. This proteome is highly conserved among strains, with the exception of a handful of proteins that are enriched differently depending on the drug responsible for induction of antimicrobial resistance. Furthermore, we obtained the first snapshot of proteins enriched in EVs released by antimony-, miltefosine- and amphotericin-resistant parasites. These include several virulence factors, transcription factors, as well as proteins encoded by drug-resistance genes. This detailed study of L. infantum EVs sheds new light on the potential roles of EVs in Leishmania biology, particularly with respect to the parasite's survival in stressful conditions. This work outlines a crucial first step towards the discovery of EV-based profiles capable of predicting response to antileishmanial agents.


Assuntos
Antiprotozoários/farmacologia , Resistência a Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/metabolismo , Biologia Computacional , Vesículas Extracelulares , Regulação da Expressão Gênica/fisiologia , Proteoma , Proteômica , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo
3.
PLoS Negl Trop Dis ; 14(7): e0008429, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32687498

RESUMO

BACKGROUND: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. CONCLUSIONS/SIGNIFICANCE: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Incidência , Índia/epidemiologia , Leishmaniose Cutânea/patologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Adulto Jovem
4.
Mem Inst Oswaldo Cruz ; 115: e190469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32638832

RESUMO

BACKGROUND Oxidative stress is responsible for generating DNA lesions and the 8-oxoguanine (8-oxoG) is the most commonly lesion found in DNA damage. When this base is incorporated during DNA replication, it could generate double-strand DNA breaks and cellular death. MutT enzyme hydrolyzes the 8-oxoG from the nucleotide pool, preventing its incorporation during DNA replication. OBJECTIVES To investigate the importance of 8-oxoG in Leishmania infantum and L. braziliensis, in this study we analysed the impact of heterologous expression of Escherichia coli MutT (EcMutT) enzyme in drug-resistance phenotype and defense against oxidative stress. METHODS Comparative analysis of L. braziliensis and L. infantum H2O2 tolerance and cell cycle profile were performed. Lines of L. braziliensis and L. infantum expressing EcMutT were generated and evaluated using susceptibility tests to H2O2 and SbIII, cell cycle analysis, γH2A western blotting, and BrdU native detection assay. FINDINGS Comparative analysis of tolerance to oxidative stress generated by H2O2 showed that L. infantum is more tolerant to exogenous H2O2 than L. braziliensis. In addition, cell cycle analysis showed that L. infantum, after treatment with H2O2, remains in G1 phase, returning to its normal growth rate after 72 h. In contrast, after treatment with H2O2, L. braziliensis parasites continue to move to the next stages of the cell cycle. Expression of the E. coli MutT gene in L. braziliensis and L. infantum does not interfere in parasite growth or in susceptibility to SbIII. Interestingly, we observed that L. braziliensis EcMutT-expressing clones were more tolerant to H2O2 treatment, presented lower activation of γH2A, a biomarker of genotoxic stress, and lower replication stress than its parental non-transfected parasites. In contrast, the EcMutT is not involved in protection against oxidative stress generated by H2O2 in L. infantum. MAIN CONCLUSIONS Our results showed that 8-oxoG clearance in L. braziliensis is important to avoid misincorporation during DNA replication after oxidative stress generated by H2O2.


Assuntos
Antimônio/toxicidade , Proteínas de Escherichia coli/genética , Escherichia coli , Guanina/análogos & derivados , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Pirofosfatases , Superóxido Dismutase/metabolismo , Animais , Antiprotozoários/farmacologia , Proteínas de Escherichia coli/metabolismo , Guanina/farmacologia , Humanos , Peróxido de Hidrogênio/toxicidade , Leishmania braziliensis/enzimologia , Leishmania infantum/enzimologia , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pirofosfatases/genética , Pirofosfatases/metabolismo , Coelhos , Ratos , Superóxido Dismutase/genética
5.
Ann Parasitol ; 66(2): 165-174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32592455

RESUMO

Neither physiological nor pathological changes following treatments explained why trypanosomes in the same group of experimentally treated animals correlated in virulence. Also, they behaved like each other but not similar to other groups despite the same T. evansi injected strain. The current study aims to discuss whether molecular changes might occur to Trypanosoma evansi isolates followed treatments are responsible for that difference or not. Ten preserved isolates from T. evansi after previous treatments besides the original strain of T. evansi that injected before treatments were used in the present study. These isolates were intraperitoneally inoculated in 11 groups of male Wister Albino rats with equal doses. Parasitological findings and the molecular changes accompanied were discussed along with the experiment based on PCR-TR3/TR4 specific-primers. The study also achieved alignments, gene sequence and phylogenetic analysis for submitted and reference strains belong to T. evansi, T. brucei, T. b. brucei, and T. b. gambiense deposited in GenBank. The present results assessed molecularly the effectiveness and highly antitrypanosomal activity of human plasmas O+ and A+ on T. evansi than others, and how their strains drifted from its original sequence to the nearest form of T. brucei. At the same time, T. evansi in other plant extract groups multiplied progressively like cancer cells and became more virulent and close to reference strains of T. evansi. Our data further indicated that T. evansi after treatment was a paraphyletic group. It also corroborated the antitrypanosomal activityspecificity and the molecular changes occurring were correlated to the type of treatment.


Assuntos
Antiprotozoários , Trypanosoma , Tripanossomíase , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Humanos , Masculino , Filogenia , Ratos , Ratos Wistar , Trypanosoma/efeitos dos fármacos , Trypanosoma/genética , Trypanosoma/patogenicidade , Tripanossomíase/sangue , Tripanossomíase/tratamento farmacológico
6.
Exp Parasitol ; 216: 107940, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562606

RESUMO

Therapeutic options for the treatment of leishmaniasis are insufficient and need improvements owing to their low efficiency and high toxicity as well as the emergence of resistant strains. The limited number of new drugs for neglected diseases and lack of innovation in your development are still challenges. In this context, the process of discovery and development of biological assays play a pivotal role for the identification of bioactive compounds. The assays currently used for screening of drugs with cytotoxic activity against Leishmania parasites, include different processes that utilize intact parasite (free or intracellular) or specific enzymes of metabolism as a target cell. These assays allow the screening of large numbers of samples followed by more detailed secondary confirmatory assays to confirm the observed activity and assess their toxicity. In the present study, we described the development of a new functional and more complete assay that enables simultaneous assessment of potential anti-Leishmania compounds through evaluation of internalization of fluorescein-labeled L. braziliensis promastigotes by human peripheral blood monocytes and their cytotoxicity by flow cytometry. We standardized the conditions for parasite labeling to achieve better phagocytosis analysis by setting the ratio of number of parasites per cell as 1 to 2, at incubation time of 6h. The cytotoxicity assessment was performed by the quantification of cells undergoing early/late apoptosis and necrosis using a double labelling platform employing 7AAD for late apoptosis and necrosis analysis and Annexin-V for early apoptosis evaluation. Hemolysis analysis was an additional parameter to test cytotoxicity. Two drugs used on clinic (Amphotericin B and Glucantime®) were used to validate the proposed methodology, and the assay was able to detect their known leishmanicidal activity and immunotoxicity properties. This new predictive assay will contribute to the development of translational medicine strategies in drug discovery for neglected diseases such as leishmaniasis.


Assuntos
Alternativas aos Testes com Animais/métodos , Antiprotozoários/toxicidade , Citometria de Fluxo/métodos , Leishmania/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Adulto , Anfotericina B/farmacologia , Anfotericina B/toxicidade , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Humanos , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Leucócitos/parasitologia , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/toxicidade , Microscopia Confocal , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/parasitologia , Fatores de Tempo , Adulto Jovem
7.
Exp Parasitol ; 216: 107943, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32598890

RESUMO

The search for novel therapeutic candidates against animal trypanosomiasis is an ongoing scientific endevour because of the negative impacts of the disease to the African livestock industry. In this study, the in vivo therapeutic potentials of phytol toward Trypanosoma congolense infection and the inhibitory effects on trypanosomal sialidase were investigated. Rats were infected with T. congolense and administered daily oral treatment of 50 and 100 mg/kg BW of phytol. Within the first 10 days of the treatment, no antitrypanosomal activity was recorded but a moderate trypanostatic activity was observed from day 17-day 21 pi. However, at 100 mg/kg BW, phytol demonstrated a significant (p < 0.05) ameliorative potentials toward T. congolense-induced host-associated pathological damages such as anaemia, hepatic and renal damages; and the data was comparable to diminazine aceturate. Moreover, the T. congolense caused a significant (p < 0.05) increase in free serum sialic acid level which was significantly (p < 0.05) prevented in the presence of phytol (100 mg/kg BW). In an in vitro analysis, phytol inhibited partially purified T. congolense sialidase using an uncompetitive inhibition pattern with inhibition binding constant of 261.24 µmol/mL. Subsequently, molecular docking revealed that the compound binds to homology modelled trypanosomal sialidase with a binding free energy of -6.7 kcal/mol which was mediated via a single hydrogen bond while Trp324 and Pro274 were the critical binding residues. We concluded that phytol has moderate trypanostatic activity but with a great potential in mitigating the host-associated cellular damages while the anaemia amelioration was mediated, in part, through the inhibition of sialidase.


Assuntos
Antiprotozoários/uso terapêutico , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Fitol/uso terapêutico , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/veterinária , Animais , Antiprotozoários/farmacologia , Inibidores Enzimáticos/uso terapêutico , Gado , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/veterinária , Neuraminidase/química , Neuraminidase/isolamento & purificação , Fitol/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/tratamento farmacológico
8.
Ann Parasitol ; 62(2): 157-163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32531148

RESUMO

Leishmaniosis is one of the most serious public health concern with a worldwide distribution. Since the current treatments of leishmaniosis are toxic and expensive, frequent studies have been conducted to investigate the benefits of new resources such as medicinal plants for treatment of this infectious disease. Recent studies revealed the antiparasitic potential of Rhus coriaria. Here we investigated the potential antileishmanial and antibacterial activities of the hydroalcoholic extract of R. coriaria fruits. The fruits were extracted using 80% methanol by maceration method. The concentrations of 312, 156, 78, and 37 µg/ml of the extract were added separately to the wells containing Leishmania major (L. major) promastigotes and amastigotes. Amphotericin B was considered as positive control. Finally, the death rate was determined for the extract-treated parasites as compared to the non-treated parasite. The antibacterial activity was evaluated by measurement of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the extract against a set of Gram-positive and Gram-negative bacteria. The extract significantly inhibited the growth of both promastigotes (60,7%) and amastigotes (59%) at the concentration of 312 µg/ml with the IC50 values of 147 µg/ml and 233 µg/ml, respectively. The extract showed bactericidal effects against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Acinetobacter baumannii. Totally, Grampositive bacteria were more susceptible to the extract. Our findings show that the hydroalcoholic extract of R. coriaria fruits are rich in tannins and can be considered for further in vivo studies on the antileishmanial and antibacterial activities especially on dermal lesions caused by L. major.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Extratos Vegetais/farmacologia , Rhus/química , Frutas/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Leishmania major/efeitos dos fármacos
9.
Parasitol Res ; 119(8): 2587-2595, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32524267

RESUMO

Lycorine is an Amaryllidaceae alkaloid that presents anti-Trichomonas vaginalis activity. T. vaginalis causes trichomoniasis, the most common non-viral sexually transmitted infection. The modulation of T. vaginalis purinergic signaling through the ectonucleotidases, nucleoside triphosphate diphosphohydrolase (NTPDase), and ecto-5'-nucleotidase represents new targets for combating the parasite. With this knowledge, the aim of this study was to investigate whether NTPDase and ecto-5'-nucleotidase inhibition by lycorine could lead to extracellular ATP accumulation. Moreover, the lycorine effect on the reactive oxygen species (ROS) production by neutrophils and parasites was evaluated as well as the alkaloid toxicity. The metabolism of purines was assessed by HPLC. ROS production was measured by flow cytometry. Cytotoxicity against epithelial vaginal cells and fibroblasts was tested, as well as the hemolytic effect of lycorine and its in vivo toxicity in Galleria mellonella larvae. Our findings showed that lycorine caused ATP accumulation due to NTPDase inhibition. The alkaloid did not affect the ROS production by T. vaginalis; however, it increased ROS levels in neutrophils incubated with lycorine-treated trophozoites. Lycorine was cytotoxic against vaginal epithelial cells and fibroblasts; conversely, it was not hemolytic neither exhibited toxicity against the in vivo model of G. mellonella larvae. Overall, besides having anti-T. vaginalis activity, lycorine modulates ectonucleotidases and stimulates neutrophils to secrete ROS. This mechanism of action exerted by the alkaloid could enhance the susceptibility of T. vaginalis to host immune cell, contributing to protozoan clearance.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Amaryllidaceae/química , Antiprotozoários/farmacologia , Neutrófilos/metabolismo , Nucleosídeo-Trifosfatase/antagonistas & inibidores , Fenantridinas/farmacologia , Extratos Vegetais/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Tricomoníase/metabolismo , Trichomonas vaginalis/enzimologia , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Humanos , Neutrófilos/efeitos dos fármacos , Nucleosídeo-Trifosfatase/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/crescimento & desenvolvimento , Trichomonas vaginalis/metabolismo , Trofozoítos/efeitos dos fármacos , Trofozoítos/enzimologia , Trofozoítos/crescimento & desenvolvimento , Trofozoítos/metabolismo
10.
Rev Soc Bras Med Trop ; 53: e20200040, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578710

RESUMO

Mucocutaneous leishmaniasis (MCL) is a chronic infection that can affect the skin and mucous membranes. We report a case of oral, nasopharyngeal, and penile lesions in a 35-year-old cocaine user. The patient presented with ulcerated lesions in 2014. Histopathologic analysis revealed amastigotes, and serological test results were positive for leishmaniasis. Systemic therapy with meglumine antimoniate was administered; however, the patient failed to present for follow-up. In 2018, he returned with nasal collapse, and another histopathologic test confirmed MCL. This case illustrates the importance of careful differential diagnosis of skin and mucous ulcers to identify the particular pathology.


Assuntos
Antiprotozoários/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/complicações , Leishmaniose Mucocutânea/diagnóstico , Antimoniato de Meglumina/administração & dosagem , Adulto , Humanos , Leishmaniose Mucocutânea/complicações , Leishmaniose Mucocutânea/tratamento farmacológico , Masculino
11.
Rev Soc Bras Med Trop ; 53: e20200091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578713

RESUMO

INTRODUCTION: The drugs currently available for leishmaniasis treatment have major limitations. METHODS: In vitro and in vivo studies were performed to evaluate the effect of a quinoline derivative, Hydraqui (7-chloro-4-(3-hydroxy-benzilidenehydrazo)quinoline, against Leishmania amazonensis. In silico analyses of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were performed. RESULTS: Hydraqui showed significant in vitro anti-amastigote activity. Also, Hydraqui-treated mice exhibited high efficacy in lesion size (48.3%) and parasitic load (93.8%) reduction, did not cause hepatic and renal toxicity, and showed appropriate ADMET properties. CONCLUSIONS: Hydraqui presents a set of satisfactory criteria for its application as an antileishmanial agent.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Quinolinas/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Leishmaniose Cutânea/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Quinolinas/química
12.
Planta Med ; 86(11): 782-789, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32512613

RESUMO

Ten lignans (1:  - 10: ) were isolated from the hexane-ethyl acetate extract of Phyllanthus amarus leaves. Three of them, cubebin dimethyl ether (3: ), urinatetralin (4: ), and lintetralin (7: ) are described for the first time in this species, while phyllanthin (1: ), niranthin (2: ), 5-demethoxyniranthin (5: ), isolintetralin (6: ), hypophyllanthin (8: ), nirtetralin (9: ), and phyltetralin (10: ) have been already reported from P. amarus. Among the lignans tested against Trypanosoma cruzi intracellular amastigotes, 2: was the most active with an EC50 of 35.28 µM. Lignans 2, 5, 7: , and 9: showed inhibitory effects against Leishmania amazonensis promastigotes with EC50 of 56.34, 51.86, 23.57, and 43.27 µM, respectively. During in vitro infection assays, 5: reduced amastigotes by 91% at 103.68 µM concentration, whereas 7: and 9: reduced amastigotes by approximately 84% at 47.5 and 86.04 µM, respectively. Lignans 5, 7: , and 9: were more potent in intracellular amastigotes with EC50 of 2.76, 8.30, and 15.83 µM, respectively, than in promastigotes. CC50 for all samples was > 100 µg/mL, thus revealing low cytotoxicity against macrophages, and selectivity against the parasite. L. amazonensis promastigotes treated with compounds 2: and 9: showed decreased respiratory control of 38% and 25%, respectively, suggesting a change in mitochondrial membrane potential and lower ATP production.


Assuntos
Antiprotozoários , Leishmania mexicana , Lignanas , Phyllanthus , Extratos Vegetais
13.
PLoS Negl Trop Dis ; 14(5): e0008339, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437349

RESUMO

Trypanothione reductase (TR) is a key enzyme that catalyzes the reduction of trypanothione, an antioxidant dithiol that protects Trypanosomatid parasites from oxidative stress induced by mammalian host defense systems. TR is considered an attractive target for the development of novel anti-parasitic agents as it is essential for parasite survival but has no close homologue in humans. We report here the identification of spiro-containing derivatives as inhibitors of TR from Trypanosoma brucei (TbTR), the parasite responsible for Human African Trypanosomiasis. The hit series, identified by high throughput screening, was shown to bind TbTR reversibly and to compete with the trypanothione (TS2) substrate. The prototype compound 1 from this series was also found to impede the growth of Trypanosoma brucei parasites in vitro. The X-ray crystal structure of TbTR in complex with compound 1 solved at 1.98 Å allowed the identification of the hydrophobic pocket where the inhibitor binds, placed close to the catalytic histidine (His 461') and lined by Trp21, Val53, Ile106, Tyr110 and Met113. This new inhibitor is specific for TbTR and no activity was detected against the structurally similar human glutathione reductase (hGR). The central spiro scaffold is known to be suitable for brain active compounds in humans thus representing an attractive starting point for the future treatment of the central nervous system stage of T. brucei infections.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , NADH NADPH Oxirredutases/antagonistas & inibidores , Tolueno/análogos & derivados , Trypanosoma brucei brucei/efeitos dos fármacos , Antiprotozoários/isolamento & purificação , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/isolamento & purificação , Ensaios de Triagem em Larga Escala , NADH NADPH Oxirredutases/química , Ligação Proteica , Conformação Proteica , Tolueno/isolamento & purificação , Tolueno/farmacologia , Trypanosoma brucei brucei/enzimologia
14.
PLoS Pathog ; 16(5): e1008600, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453775

RESUMO

Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics.


Assuntos
Antiprotozoários , Apicomplexa/crescimento & desenvolvimento , Bivalves/microbiologia , Gammaproteobacteria/metabolismo , Simbiose , Animais , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Camundongos , Infecções por Protozoários/tratamento farmacológico
15.
Int J Infect Dis ; 97: 27-29, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32425641

RESUMO

BACKGROUND: Visceral leishmaniasis-related hemophagocytic lymphohistiocytosis (VL-HLH) is a secondary hemophagocytic syndrome, which can be life-threatening, caused by leishmania and transmitted by infected sandflies. Rapid and accurate identification of leishmania is crucial for clinical strategies. CASE REPORT: Here, we report an infantile infection in a non-epidemic area of China. The infant was a 9.5-month-old girl with fever, pancytopenia and hepatosplenomegaly, which meet the HLH-2004 standard, and the negative gene results exclude congenital HLH. However, chemotherapy is ineffective and is accompanied by severe infection. Fortunately, she is diagnosed with VL-HLH (visceral leishmaniasis-related hemophagocytic lymphohistiocytosis), as leishmania is detected by next-generation meta-genome sequencing (mNGS) and quickly relieved after treatment with libosomal amphotericin B (L-AMB). CONCLUSION: mNGS can detect leishmania in pediatric HLH, and should be performed as a new detection for VL-HLH, particularly for infants, who may not respond to HLH-2004 regimen.


Assuntos
Leishmaniose Visceral/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Leishmania/isolamento & purificação , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/parasitologia
16.
Parasitol Res ; 119(7): 2263-2274, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32462293

RESUMO

Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which makes the development of new drugs urgent. To achieve this goal, the integration of kinetic and DSF assays against parasitic validated targets, along with phenotypic assays, can help the identification and optimization of bioactive compounds. Pteridine reductase 1 (PTR1), a validated target in Leishmania sp., is responsible for the reduction of folate and biopterin to tetrahydrofolate and tetrahydrobiopterin, respectively, both of which are essential for cell growth. In addition to the in vitro evaluation of 16 thiazolidine-2,4-dione derivatives against Leishmania major PTR1 (LmPTR1), using the differential scanning fluorimetry (ThermoFluor®), phenotypic assays were employed to evaluate the compound effect over Leishmania braziliensis (MHOM/BR/75/M2903) and Leishmania infantum (MHOM/BR/74/PP75) promastigotes viability. The ThermoFluor® results show that thiazolidine-2,4-dione derivatives have micromolar affinity to the target and equivalent activity on Leishmania cells. 2b is the most potent compound against L. infantum (EC50 = 23.45 ± 4.54 µM), whereas 2a is the most potent against L. braziliensis (EC50 = 44.16 ± 5.77 µM). This result suggests that lipophilic substituents on either-meta and/or-para positions of the benzylidene ring increase the potency against L. infantum. On the other hand, compound 2c (CE50 = 49.22 ± 7.71 µM) presented the highest selectivity index.


Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Antiprotozoários/química , Humanos , Leishmania braziliensis/enzimologia , Leishmania infantum/enzimologia , Oxirredutases/antagonistas & inibidores , Testes de Sensibilidade Parasitária , Tiazolidinedionas/química
17.
Parasitol Res ; 119(6): 1857-1871, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32350589

RESUMO

Antimony is an important drug for the treatment of Leishmania parasite infections. In several countries, the emergence of drug-resistant Leishmania species has reduced the effectiveness of this drug. The mechanism of clinical drug resistance is unclear. The aim of this work was to identify mitochondrial proteome alterations associated with resistance against antimonial. A combination of cell fractionation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and Label-Free Quantification was used to characterize the mitochondrial protein composition of Leishmania tropica field isolates resistant and sensitive to meglumine antimoniate. LC-MS/MS analysis resulted in the identification of about 1200 proteins of the Leishmania tropica mitochondrial proteome. Various criteria were used to allocate about 40% proteins to mitochondrial proteome. Comparative quantitative proteomic analysis of the sensitive and the resistant strains showed proteins with differential abundance in resistance species are involved in TCA and aerobic respiration enzymes, stress proteins, lipid metabolism enzymes, and translation. These results showed that the mechanism of antimony resistance in Leishmania spp. field isolate may be associated with alteration in enzymes involved in mitochondrial pathways.


Assuntos
Antiprotozoários/farmacologia , Leishmania tropica/efeitos dos fármacos , Antimoniato de Meglumina/farmacologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Linhagem Celular , Cromatografia Líquida , Resistência a Medicamentos , Leishmania tropica/isolamento & purificação , Leishmania tropica/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Proteoma , Proteômica , Espectrometria de Massas em Tandem
18.
Am J Trop Med Hyg ; 103(1): 308-314, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32394874

RESUMO

Visceral leishmaniasis (VL) is endemic in Asia, East and North Africa, South America, and Southern Europe, and is a major public health problem in the Indian subcontinent. Miltefosine received approval in 2002 to treat VL in India, and the Indian National Vector Borne Disease Control Programme later adopted a single dose (10 mg/kg) of liposomal amphotericin B. We report results of a randomized trial comparing the efficacy of combination therapy with an Indian preparation of liposomal amphotericin B (single dose of 7.5 mg/kg) and short-course miltefosine (2.5 mg/kg/day for 14 days; n = 66) in comparison to miltefosine monotherapy (2.5 mg/kg/day for 28 days; n = 78). Nine patients in the miltefosine group and three in the combination therapy group had to discontinue therapy because of serious adverse events. At the end of the therapy, the clinical and parasitological cure rate was 100% in both groups. By per-protocol analysis, by 6 months after completion of treatment, 12 of 69 patients in the miltefosine monotherapy arm (17.4%, 95% CI: 10.24-28%) and none in the combination therapy arm had relapse. Over 5 years of follow-up, 10 patients in the miltefosine monotherapy arm (all within 0.5-2 years after completing therapy) and none in the combination therapy arm experienced post-kala-azar dermal leishmaniasis. Combination therapy offered benefits over miltefosine monotherapy for VL in India.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Idoso , Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Quimioterapia Combinada , Feminino , Humanos , Índia , Leishmania donovani , Masculino , Pessoa de Meia-Idade , Fosforilcolina/administração & dosagem , Fosforilcolina/uso terapêutico , Adulto Jovem
19.
Intern Med ; 59(9): 1227-1230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32378656

RESUMO

Liposomal-amphotericin B (L-AmB) is used for cutaneous leishmaniasis (CL); however, its treatment failure has not yet been described in detail. A 58-year-old man returned from the Republic of Venezuela with a cutaneous ulcer on his left lower leg. The causative pathogen was Leishmania braziliensis. We started L-AmB 3 mg/kg/day for 6 days; however, the ulcer did not resolve. The patient was successfully retreated with a higher dose L-AmB 4 mg/kg/day 9 times (total, 36 mg/kg). If L-AmB fails to treat CL and other therapeutics cannot be used, increasing the L-AmB dose is a viable option.


Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania braziliensis/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Humanos , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Retratamento , Falha de Tratamento
20.
Hautarzt ; 71(6): 437-442, 2020 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-32394080

RESUMO

Here we describe two complicated cases of complex Old World cutaneous Leishmaniasis due to L. infantum and L. aethiopica. Both of our patients infected with the Leishmania parasite presented with a completely different clinical picture, course of disease, and treatment response. Clinical healing was achieved after multiple courses of treatment with a variety of different antileishmanial drugs. Nephrotoxity was a limiting side effect.


Assuntos
Leishmania infantum/isolamento & purificação , Leishmania/isolamento & purificação , Leishmaniose Cutânea/diagnóstico , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Progressão da Doença , Humanos , Leishmania/classificação
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