Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 673
Filtrar
1.
Indian J Med Microbiol ; 37(1): 120-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424023

RESUMO

Primary amoebic meningoencephalitis is rare but fatal disease encountered in immunocompetent individuals. Here, we present a case of a previously healthy 8-month-old female child, who presented with features of meningoencephalitis of 2 days' duration. Rapidly moving trophozoites of amoeba were observed in cerebrospinal fluid, which were confirmed to be Naegleria fowleri on polymerase chain reaction. Broad-spectrum antimicrobial therapy with ceftriaxone, vancomycin, amphotericin B and acyclovir was initiated. However, the patient deteriorated and left the hospital against medical advice. The isolation of N. fowleri in this case demands for increased awareness for prompt diagnosis and management in view of its high mortality.


Assuntos
Amebíase/diagnóstico , Amebicidas/uso terapêutico , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Meningoencefalite/parasitologia , Naegleria fowleri/isolamento & purificação , Aciclovir/uso terapêutico , Amebíase/tratamento farmacológico , Anfotericina B/uso terapêutico , Ceftriaxona/uso terapêutico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Líquido Cefalorraquidiano/parasitologia , Feminino , Humanos , Lactente , Meningoencefalite/diagnóstico , Meningoencefalite/tratamento farmacológico , Naegleria fowleri/genética , Trofozoítos/isolamento & purificação , Vancomicina/uso terapêutico
2.
Artigo em Inglês | MEDLINE | ID: mdl-31192168

RESUMO

The protozoan parasite Entamoeba histolytica can induce amebic colitis and amebic liver abscess. First-line drugs for the treatment of amebiasis are nitroimidazoles, particularly metronidazole. Metronidazole has side effects and potential drug resistance is a concern. Schistosomiasis, a chronic and painful infection, is caused by various species of the Schistosoma flatworm. There is only one partially effective drug, praziquantel, a worrisome situation should drug resistance emerge. As many essential metabolic pathways and enzymes are shared between eukaryotic organisms, it is possible to conceive of small molecule interventions that target more than one organism or target, particularly when chemical matter is already available. Farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway, is vital for diverse functions, including cell differentiation and growth. Both E. histolytica and Schistosoma mansoni genomes encode FT genes. In this study, we phenotypically screened E. histolytica and S. mansoni in vitro with the established FT inhibitors, lonafarnib and tipifarnib, and with 125 tipifarnib analogs previously screened against both the whole organism and/or the FT of Trypanosoma brucei and Trypanosoma cruzi. For E. histolytica, we also explored whether synergy arises by combining lonafarnib and metronidazole or lonafarnib with statins that modulate protein prenylation. We demonstrate the anti-amebic and anti-schistosomal activities of lonafarnib and tipifarnib, and identify 17 tipifarnib analogs with more than 75% growth inhibition at 50 µM against E. histolytica. Apart from five analogs of tipifarnib exhibiting activity against both E. histolytica and S. mansoni, 10 additional analogs demonstrated anti-schistosomal activity (severe degenerative changes at 10 µM after 24 h). Analysis of the structure-activity relationship available for the T. brucei FT suggests that FT may not be the relevant target in E. histolytica and S. mansoni. For E. histolytica, combination of metronidazole and lonafarnib resulted in synergism for growth inhibition. Also, of a number of statins tested, simvastatin exhibited moderate anti-amebic activity which, when combined with lonafarnib, resulted in slight synergism. Even in the absence of a definitive molecular target, identification of potent anti-parasitic tipifarnib analogs encourages further exploration while the synergistic combination of metronidazole and lonafarnib offers a promising treatment strategy for amebiasis.


Assuntos
Entamoeba histolytica/efeitos dos fármacos , Farnesiltranstransferase/metabolismo , Schistosoma mansoni/efeitos dos fármacos , Amebíase/tratamento farmacológico , Animais , Biomphalaria , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Tratamento Farmacológico/métodos , Farnesiltranstransferase/efeitos dos fármacos , Farnesiltranstransferase/genética , Feminino , Metronidazol/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Quinolonas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
3.
Parasit Vectors ; 12(1): 280, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159839

RESUMO

BACKGROUND: Species of Acanthamoeba are facultative pathogens which can cause sight threatening Acanthamoeba keratitis and a rare but deadly brain infection, granulomatous amoebic encephalitis. Due to conversion of Acanthamoeba trophozoites to resistant cyst stage, most drugs are found to be ineffective at preventing recurrence of infection. This study was designed to test the antiacanthamoebic effects of different cobalt nanoparticles (CoNPs) against trophozoites and cysts, as well as parasite-mediated host cell cytotoxicity. METHODS: Three different varieties of CoNPs were synthesized by utilizing hydrothermal and ultrasonication methods and were thoroughly characterized by X-ray diffraction and field emission scanning electron microscopy. Amoebicidal, encystation, excystation, and host cell cytopathogenicity assays were conducted to study the antiacanthamoebic effects of CoNPs. RESULTS: The results of the antimicrobial evaluation revealed that cobalt phosphate Co3(PO4)2 hexagonal microflakes, and 100 nm large cobalt hydroxide (Co(OH)2) nanoflakes showed potent amoebicidal activity at 100 and 10 µg/ml against Acanthamoeba castellanii as compared to granular cobalt oxide (Co3O4) of size 35-40 nm. Furthermore, encystation and excystation assays also showed consistent inhibition at 100 µg/ml. CoNPs also inhibited amoebae-mediated host cell cytotoxicity as determined by lactate dehydrogenase release without causing significant damage to human cells when treated alone. CONCLUSIONS: To our knowledge, these findings determined, for the first time, the effects of composition, size and morphology of CoNPs against A. castellanii. Co3(PO4)2 hexagonal microflakes showed the most promising antiamoebic effects as compared to Co(OH)2 nanoflakes and granular Co3O4. The results reported in the present study hold potential for the development of antiamoebic nanomedicine.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Cobalto/farmacologia , Nanopartículas/química , Amebíase/tratamento farmacológico , Células Cultivadas , Microscopia Eletrônica de Varredura , Trofozoítos/efeitos dos fármacos
4.
Drug Resist Updat ; 44: 1-14, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31112766

RESUMO

Entamoeba histolytica is the etiological agent of amebiasis, which is an endemic parasitic disease in developing countries and is the cause of approximately 70,000 deaths annually. E. histolytica trophozoites usually reside in the colon as a non-pathogenic commensal in most infected individuals (90% of infected individuals are asymptomatic). For unknown reasons, these trophozoites can become virulent and invasive, cause amebic dysentery, and migrate to the liver where they cause hepatocellular damage. Amebiasis is usually treated either by amebicides which are classified as (a) luminal and are active against the luminal forms of the parasite, (b) tissue and are effective against those parasites that have invaded tissues, and (c) mixed and are effective against the luminal forms of the parasite and those forms which invaded the host's tissues. Of the amebicides, the luminal amebicide, metronidazole (MTZ), is the most widely used drug to treat amebiasis. Although well tolerated, concerns about its adverse effects and the possible emergence of MTZ-resistant strains of E. histolytica have led to the development of new therapeutic strategies against amebiasis. These strategies include improving the potency of existing amebicides, discovering new uses for approved drugs (repurposing of existing drugs), drug rediscovery, vaccination, drug targeting of essential E. histolytica components, and the use of probiotics and bioactive natural products. This review examines each of these strategies in the light of the current knowledge on the gut microbiota of patients with amebiasis.


Assuntos
Amebíase/tratamento farmacológico , Amebíase/prevenção & controle , Amebicidas/uso terapêutico , Entamoeba histolytica/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Vacinas Protozoárias/administração & dosagem , Amebíase/imunologia , Amebíase/parasitologia , Animais , Produtos Biológicos/uso terapêutico , Colo/efeitos dos fármacos , Colo/parasitologia , Colo/patologia , Reposicionamento de Medicamentos/métodos , Entamoeba histolytica/patogenicidade , Entamoeba histolytica/fisiologia , Microbioma Gastrointestinal/imunologia , Interações Hospedeiro-Parasita/imunologia , Humanos , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Metronidazol/uso terapêutico , Interações Microbianas , Probióticos/uso terapêutico , Vacinas Protozoárias/biossíntese , Índice de Gravidade de Doença
5.
Mini Rev Med Chem ; 19(12): 980-987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30868950

RESUMO

Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as "brain-eating amoebae". The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.


Assuntos
Amebíase/tratamento farmacológico , Amebíase/parasitologia , Amoeba/efeitos dos fármacos , Encéfalo/parasitologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/parasitologia , Naegleria fowleri/efeitos dos fármacos , Naegleria fowleri/parasitologia , Amebíase/diagnóstico , Doenças do Sistema Nervoso Central/diagnóstico , Humanos
6.
Exp Parasitol ; 199: 24-29, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30796912

RESUMO

The genus Acanthamoeba, which may cause different infections in humans, occurs widely in the environment. Lung inflammation caused by these parasites induces pulmonary pathological changes such as pulmonary necrosis, peribronchial plasma cell infiltration, moderate desquamation of alveolar cells and partial destruction of bronchial epithelial cells, and presence of numerous trophozoites and cysts among inflammatory cells. The aim of this study was to assess the influence of plant extracts from Artemisia annua L. on expression of the toll-like receptors TLR2 and TLR4 in lungs of mice with acanthamoebiasis. A. annua, which belongs to the family Asteraceae, is an annual plant that grows wild in Asia. In this study, statistically significant changes of expression of TLR2 and TLR4 were demonstrated. In the lungs of infected mice after application of extract from A. annua the expression of TLRs was observed mainly in bronchial epithelial cells, pneumocytes (to a lesser extent during the outbreak of infection), and in the course of high general TLR expression. TLR4 in particular was also visible in stromal cells of lung parenchyma. In conclusion, we confirmed that a plant extract of A. annua has a modulatory effect on components of the immune system such as TLR2 and TLR4.


Assuntos
Acanthamoeba/fisiologia , Amebíase/tratamento farmacológico , Artemisia annua/química , Pneumopatias Parasitárias/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Receptores Toll-Like/metabolismo , Amebíase/metabolismo , Animais , DNA Complementar/metabolismo , Imuno-Histoquímica , Pulmão/parasitologia , Pulmão/patologia , Pneumopatias Parasitárias/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , RNA Mensageiro/metabolismo , RNA de Protozoário/genética , RNA de Protozoário/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Reversa , Receptor 2 Toll-Like/efeitos dos fármacos , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/efeitos dos fármacos , Receptores Toll-Like/genética
7.
Exp Parasitol ; 197: 29-35, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30648558

RESUMO

Free-living amoebae of the genus Acanthamoeba are the etiological agents of cutaneous lesions, granulomatous amoebic encephalitis (GAE) and amoebic keratitis (AK), which are chronic infections with poor prognosis if not diagnosed promptly. Currently, there is no optimal therapeutic scheme to eradicate the pathologies these protozoa cause. In this study we report the morphological and molecular identification of three species of the genus Acanthamoeba, belonging to T4 group; A. polyphaga isolated from the corneal ulcer of a patient sample of AK case; A. castellanii isolated from the contact lens of an AK patient and A. palestinensis obtained from a soil sample. The in vitro activity of chlorhexidine, itraconazole and voriconazole drugs against trophic stage was also evaluated through a colorimetric assay based on the oxidation-reduction of alamar blue. The strains in the study were sensitive to the evaluated drugs; although when determining the 50% inhibitory concentration (IC50) statistically significant differences were observed. A. castellanii showed to be highly sensitive to voriconazole (0.66 ±â€¯0.13 µM) but the least sensitive to chlorhexidine and itraconazole (8.61 ±â€¯1.63 and 20.14 ±â€¯4.93 µM, respectively), A. palestinensis showed the highest sensitivity to itraconazole (0.502 ±â€¯0.11 µM) and A. polyphaga expressed moderate sensitivity to chlorhexidine and itraconazole and lower sensitivity to voriconazole (10.10 ±â€¯2.21 µM). These results showed that species of the genus Acanthamoeba express different sensitivity to the tested drugs, which could explain the problems surrounding the establishment of a treatment of choice in the infections caused by these amoebae. We consider that although chlorhexidine and itraconazole show good activity on these amoebae and have been used in cases of AK in Mexico with acceptable results, voriconazole should be considered as the first therapeutic option of future Acanthamoeba infections that will be diagnosed in our country.


Assuntos
Acanthamoeba/efeitos dos fármacos , Amebíase/parasitologia , Anti-Infecciosos/farmacologia , Clorexidina/farmacologia , Itraconazol/farmacologia , Voriconazol/farmacologia , Acanthamoeba/classificação , Acanthamoeba/genética , Ceratite por Acanthamoeba/parasitologia , Amebíase/tratamento farmacológico , Lentes de Contato/parasitologia , Úlcera da Córnea/parasitologia , DNA de Protozoário/isolamento & purificação , Genótipo , Humanos , Concentração Inibidora 50 , México , Solo/parasitologia
8.
Curr Drug Targets ; 20(1): 60-69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29697029

RESUMO

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.


Assuntos
Amebíase/tratamento farmacológico , Amoeba/efeitos dos fármacos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Descoberta de Drogas/métodos , Encefalite Infecciosa/tratamento farmacológico , Proteínas de Protozoários/antagonistas & inibidores , Amebíase/parasitologia , Amoeba/metabolismo , Animais , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Biologia Computacional , Modelos Animais de Doenças , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Encefalite Infecciosa/parasitologia , Terapia de Alvo Molecular/métodos , Proteínas de Protozoários/metabolismo
9.
Turk J Pediatr ; 60(3): 340-343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30511552

RESUMO

Sütçü M, Aktürk H, Gülümser-Sisko S, Acar M, Erol OB, Somer A, Bilgiç B, Salman N. Granulomatous amebic encephalitis caused by Acanthamoeba in an immuncompetent child. Turk J Pediatr 2018; 60: 340-343. Acanthamoeba may lead to granulomatous amebic encephalitis (GAE) with high mortality rates generally in patients with immunosupression and/or chronic disease. Here, we present a rare GAE case, who was a previously healthy child. A Georgian 9 year old boy presented with focal seizure on his left arm and confusion. Since computed tomography (CT) demonstrated hypodense lesion on right occipital lobe, brain biopsy was performed. Histopathological examination of the biopsy material revealed Acanthamoeba cysts and trophozoites together with granulomatous inflammation. The patient, who had no clinical and laboratory findings consistent with immunedeficiency, was diagnosed as GAE. He was treated with a combination drug therapy. Even if it is very rare, amebic meningoencephalitis may also be seen in immunocompetent children, as in our case. Definitive diagnosis is made by microbiological and histopathological examination of brain biopsy material.


Assuntos
Acanthamoeba/isolamento & purificação , Amebíase/diagnóstico , Anti-Infecciosos/uso terapêutico , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Encefalite Infecciosa/diagnóstico , Amebíase/tratamento farmacológico , Animais , Encéfalo/parasitologia , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Criança , Quimioterapia Combinada , Evolução Fatal , Granuloma/diagnóstico , Humanos , Encefalite Infecciosa/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X
10.
Artigo em Inglês | MEDLINE | ID: mdl-30568921

RESUMO

Amebiasis is caused by infection with the protozoan parasite Entamoeba histolytica. Although metronidazole has been a drug of choice against amebiasis for decades, it shows side effects and low efficacy against asymptomatic cyst carriers. In addition, metronidazole resistance has been documented for bacteria and protozoa that share its targets, anaerobic energy metabolism. Therefore, drugs with new mode of action or targets are urgently needed. L-cysteine is the major thiol and an essential amino acid for proliferation and anti-oxidative defense of E. histolytica trophozoites. E. histolytica possesses the de novo L-cysteine biosynthetic pathway, consisting of two reactions catalyzed by serine acetyltransferase and cysteine synthase (CS, O-acetylserine sulfhydrylase). As the pathway is missing in humans, it is considered to be a rational drug target against amebiasis. In this study, we established a protocol to screen both a library of structurally known compounds and microbial culture extracts to discover compounds that target de novo cysteine biosynthesis of E. histolytica. The new screening system allowed us to identify the compounds that differentially affect the growth of the trophozoites in the cysteine-deprived medium compared to the cysteine-containing medium. A total of 431 structurally defined compounds of the Kitasato Natural Products Library and 6,900 microbial culture broth extracts were screened on the system described above. Five compounds, aspochalasin B, chaetoglobosin A, prochaetoglobosin III, cerulenin, and deoxyfrenolicin, from the Kitasato Natural Products Library, showed differential antiamebic activities in the cysteine-deprived medium when compared to the growth in the cysteine-containing medium. The selectivity of three cytochalasans apparently depends on their structural instability. Eleven microbial extracts showed selective antiamebic activities, and one fungal secondary metabolite, pencolide, was isolated. Pencolide showed cysteine deprivation-dependent antiamebic activity (7.6 times lower IC50 in the absence of cysteine than that in the presence of cysteine), although the IC50 value in the cysteine-deprived medium was rather high (283 µM). Pencolide also showed inhibitory activity against both CS1 and CS3 isoenzymes with comparable IC50 values (233 and 217 µM, respectively). These results indicated that antiamebic activity of pencolide is attributable to inhibition of CS. Cytotoxicity of pencolide was 6.7 times weaker against mammalian MRC-5 cell line than E. histotytica. Pencolide has the maleimide structure, which is easily attacked by Michael donors including the thiol moiety of cysteine. The cysteine-adducts of pencolide were detected by mass spectrometric analysis as predicted. As CS inhibition by the pencolide adducts was weak and their IC50 values to CS was comparable to that to the parasite in the cysteine-containing medium, the cysteine-adducts of pencolide likely contribute to toxicity of pencolide to the parasite in the cysteine-rich conditions. However, we cannot exclude a possibility that pencolide inactivates a variety of targets other than CSs in the absence of cysteine. Taken together, pencolide is the first compound that inhibits CS and amebic cell growth in a cysteine-dependent manner with relatively low mammalian cytotoxicity.


Assuntos
Antiprotozoários/farmacologia , Cisteína Sintase/efeitos dos fármacos , Entamoeba histolytica/efeitos dos fármacos , Entamoeba histolytica/metabolismo , Amebíase/tratamento farmacológico , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Vias Biossintéticas , Linhagem Celular/efeitos dos fármacos , Cisteína , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Entamoeba histolytica/genética , Fibroblastos/efeitos dos fármacos , Humanos , Oxirredução , Metabolismo Secundário , Trofozoítos/metabolismo
11.
mBio ; 9(5)2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30377287

RESUMO

Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris-a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions-have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections.IMPORTANCE Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This report addresses the need for new treatment options through a drug repurposing screen to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at pharmacologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings that we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life-threatening B. mandrillaris infections.


Assuntos
Amebicidas/farmacologia , Balamuthia mandrillaris/efeitos dos fármacos , Nitroquinolinas/farmacologia , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Amebíase/patologia , Balamuthia mandrillaris/crescimento & desenvolvimento , Encéfalo/parasitologia , Encéfalo/patologia , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/parasitologia , Fibroblastos/patologia , Humanos , Modelos Biológicos , Testes de Sensibilidade Parasitária
12.
PLoS Pathog ; 14(10): e1007295, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30308066

RESUMO

Amebiasis, a global intestinal parasitic disease, is due to Entamoeba histolytica. This parasite, which feeds on bacteria in the large intestine of its human host, can trigger a strong inflammatory response upon invasion of the colonic mucosa. Whereas information about the mechanisms which are used by the parasite to cope with oxidative and nitrosative stresses during infection is available, knowledge about the contribution of bacteria to these mechanisms is lacking. In a recent study, we demonstrated that enteropathogenic Escherichia coli O55 protects E. histolytica against oxidative stress. Resin-assisted capture (RAC) of oxidized (OX) proteins coupled to mass spectrometry (OX-RAC) was used to investigate the oxidation status of cysteine residues in proteins present in E. histolytica trophozoites incubated with live or heat-killed E. coli O55 and then exposed to H2O2-mediated oxidative stress. We found that the redox proteome of E. histolytica exposed to heat-killed E. coli O55 is enriched with proteins involved in redox homeostasis, lipid metabolism, small molecule metabolism, carbohydrate derivative metabolism, and organonitrogen compound biosynthesis. In contrast, we found that proteins associated with redox homeostasis were the only OX-proteins that were enriched in E. histolytica trophozoites which were incubated with live E. coli O55. These data indicate that E. coli has a profound impact on the redox proteome of E. histolytica. Unexpectedly, some E. coli proteins were also co-identified with E. histolytica proteins by OX-RAC. We demonstrated that one of these proteins, E. coli malate dehydrogenase (EcMDH) and its product, oxaloacetate, are key elements of E. coli-mediated resistance of E. histolytica to oxidative stress and that oxaloacetate helps the parasite survive in the large intestine. We also provide evidence that the protective effect of oxaloacetate against oxidative stress extends to Caenorhabditis elegans.


Assuntos
Entamoeba histolytica/efeitos dos fármacos , Entamebíase/tratamento farmacológico , Escherichia coli/fisiologia , Ácido Oxaloacético/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Amebíase/tratamento farmacológico , Amebíase/metabolismo , Amebíase/parasitologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/parasitologia , Células Cultivadas , Entamebíase/metabolismo , Entamebíase/parasitologia , Células HeLa , Humanos , Intestino Grosso/efeitos dos fármacos , Intestino Grosso/metabolismo , Intestino Grosso/parasitologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA
13.
Parasitol Res ; 117(11): 3519-3525, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30112674

RESUMO

Free-living amoebae belonging to Acanthamoeba genus are widely distributed protozoans which are able to cause infection in humans and other animals such as keratitis and encephalitis. Acanthamoeba keratitis is a vision-threatening corneal infection with currently no available fully effective treatment. Moreover, the available therapeutic options are insufficient and are very toxic to the eye. Therefore, there is an urgent need for the development of more effective anti-amoebic agents. Nanotechnology approaches have been recently reported to be useful for the elucidation antimicrobial, antiviral, antifungal and antiprotozoal activities and thus, they could be a good approach for the development of anti-Acanthamoeba agents. Therefore, this study was aimed to explore the activity and cytotoxicity of tannic acid-modified silver nanoparticles, pure silver nanoparticles and pure gold nanoparticles against clinical strains of Acanthamoeba spp. The obtained results showed a significant anti-amoebic effect of the tannic acid-modified silver nanoparticles which also presented low cytotoxicity. Moreover, tannic acid-modified silver nanoparticles were well absorbed by the trophozoites and did not induce encystation. On the other hand, pure silver nanoparticles were only slightly active against the trophozoite stage and pure gold nanoparticles did not show any activity. In conclusion and based on the observed results, silver nanoparticle conjugation with tannic acid may be considered as potential agent against Acanthamoeba spp.


Assuntos
Ceratite por Acanthamoeba/tratamento farmacológico , Acanthamoeba/efeitos dos fármacos , Amebíase/tratamento farmacológico , Antiprotozoários/uso terapêutico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Encefalite Infecciosa/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Taninos/uso terapêutico , Ceratite por Acanthamoeba/parasitologia , Amebíase/parasitologia , Amoeba/efeitos dos fármacos , Animais , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Ouro/farmacologia , Humanos , Encefalite Infecciosa/parasitologia , Prata/farmacologia , Trofozoítos/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-29967024

RESUMO

trans-Cinnamic acid (CA) is a natural organic compound. Using amoebicidal assays, for the first time we showed that CA affected the viability of the protist pathogen Acanthamoeba castellanii Conjugation with gold nanoparticles (AuNPs) enhanced the antiamoebic effects of CA. CA-coated AuNPs (CA-AuNPs) also exhibited significant excystation and encystation activity, compared to CA and AuNPs alone. Pretreatment of amoebae with CA-AuNPs inhibited A. castellanii-mediated host cell cytotoxicity. Moreover, CA-AuNPs exhibited potent effects against methicillin-resistant Staphylococcus aureus and neuropathogenic Escherichia coli K1 and protected host cells against bacteria-mediated host cell death.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Antibacterianos/farmacologia , Cinamatos/farmacologia , Ouro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos
15.
Sci Rep ; 8(1): 8520, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29867132

RESUMO

Amoebae of the genus Acanthamoeba are ubiquitous protists that have been isolated from many sources such as soils, water and the air. They are responsible for infections including fatal encephalitis and a severe keratitis in humans. To date, there is no satisfactorily effective therapeutic agent against this pathogen and the infections it causes are exacerbated by the existence of a resistant cyst stage produced by this amoeba. As dry eye syndrome is a risk factor for Acanthamoeba keratitis, we aimed to evaluate the anti-Acanthamoeba activity of a variety of proprietary eye drops intended to treat dry eye syndrome. From the nine eye drop formulations tested, "Systane Ultra" was determined to be the most active against all tested Acanthamoeba strains. During our investigations into the mode of action of Systane Ultra, we discovered that it decreases mitochondrial membrane potential and ATP levels, induces chromatin condensation, and increases the permeability of the plasma-membrane.


Assuntos
Acanthamoeba/metabolismo , Amebíase/tratamento farmacológico , Amebicidas/farmacologia , Síndromes do Olho Seco/tratamento farmacológico , Ceratose/tratamento farmacológico , Soluções Oftálmicas/farmacologia , Síndromes do Olho Seco/parasitologia , Humanos , Ceratose/parasitologia
16.
Infect Dis Poverty ; 7(1): 34, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29699585

RESUMO

BACKGROUND: Primary pulmonary amoeba is very rare and here we report a case of a 68-year-old man presenting with primary pulmonary amoeba after undergoing chemotherapy for lung adenocarcinoma. CASE PRESENTATION: In October 2016, the man aged 68 was admitted to our hospital because of repeated cough for 8 months and hemoptysis for 1 month. He was diagnosed lung adenocarcinoma and underwent surgery in 2012 without receiving chemotherapy. In March 2016, the patients suffered recurrence of cancer and was treated with chemotherapy. After 2 months of chemotherapy, the patient had consistent cough with white sputum, and chest CT showed a local lung nodule. The physicians suspected that the patient had pulmonary infectious diseases, and he was treated with empirical antibacterial treatment. However, his symptom wasn't relieved and later the percutaneous lung biopsy found trophozites of Entamoeba histolytica. After administration of metronidazole, the symptoms of the patient were markedly relieved and the lesions were absorbed. CONCLUSIONS: In such cases where patients with pulmonary nodules were in immunodeficiency state and had adequate but ineffective anti-bacterial treatment, Entamoeba histolytica infection could be one of the rare causes. Percutaneous lung biopsy should be recommended and specific dying for parasites should be done when necessary.


Assuntos
Amebíase/diagnóstico , Antiprotozoários/uso terapêutico , Entamoeba histolytica/isolamento & purificação , Pneumopatias Parasitárias/diagnóstico , Metronidazol/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Idoso , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Antineoplásicos/uso terapêutico , China , Humanos , Pneumopatias Parasitárias/tratamento farmacológico , Pneumopatias Parasitárias/parasitologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Masculino
17.
Int J Parasitol Drugs Drug Resist ; 8(1): 125-136, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29518650

RESUMO

The Coenzyme A (CoA), as a cofactor involved in >100 metabolic reactions, is essential to the basic biochemistry of life. Here, we investigated the CoA biosynthetic pathway of Entamoeba histolytica (E. histolytica), an enteric protozoan parasite responsible for human amebiasis. We identified four key enzymes involved in the CoA pathway: pantothenate kinase (PanK, EC 2.7.1.33), bifunctional phosphopantothenate-cysteine ligase/decarboxylase (PPCS-PPCDC), phosphopantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK). Cytosolic enzyme PanK, was selected for further biochemical, genetic, and phylogenetic characterization. Since E. histolytica PanK (EhPanK) is physiologically important and sufficiently divergent from its human orthologs, this enzyme represents an attractive target for the development of novel anti-amebic chemotherapies. Epigenetic gene silencing of PanK resulted in a significant reduction of PanK activity, intracellular CoA concentrations, and growth retardation in vitro, reinforcing the importance of this gene in E. histolytica. Furthermore, we screened the Kitasato Natural Products Library for inhibitors of recombinant EhPanK, and identified 14 such compounds. One compound demonstrated moderate inhibition of PanK activity and cell growth at a low concentration, as well as differential toxicity towards E. histolytica and human cells.


Assuntos
Antiprotozoários/isolamento & purificação , Vias Biossintéticas/efeitos dos fármacos , Entamoeba histolytica/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/isolamento & purificação , Amebíase/tratamento farmacológico , Produtos Biológicos , Vias Biossintéticas/genética , Coenzima A/análise , Coenzima A/biossíntese , Coenzima A/genética , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Entamoeba histolytica/efeitos dos fármacos , Entamoeba histolytica/genética , Entamoeba histolytica/crescimento & desenvolvimento , Epigenômica , Inativação Gênica , Humanos , Nucleotidiltransferases/genética , Nucleotidiltransferases/isolamento & purificação , Peptídeo Sintases/genética , Peptídeo Sintases/isolamento & purificação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Filogenia , Bibliotecas de Moléculas Pequenas
20.
Transpl Infect Dis ; 20(2): e12843, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29359845

RESUMO

Acanthamoeba infections are difficult to diagnose and treat. We present a renal transplant patient who developed Acanthamoeba endophthalmitis on therapy with posaconazole and miltefosine for cutaneous acanthamobiasis. The patient was maintained on intracameral voriconazole injections, and oral azithromycin, fluconazole, and flucytosine. This case highlights novel presentations and treatments for acanthamoebic infection.


Assuntos
Amebíase/tratamento farmacológico , Amebicidas/uso terapêutico , Endoftalmite/parasitologia , Transplante de Rim , Dermatopatias Parasitárias/tratamento farmacológico , Amebíase/etiologia , Amebicidas/administração & dosagem , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Endoftalmite/tratamento farmacológico , Endoftalmite/patologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Dermatopatias Parasitárias/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA