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2.
Exp Parasitol ; 218: 108008, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32979343

RESUMO

Acanthamoeba sp. is a free living amoeba that causes severe, painful and fatal infections, viz. Acanthamoeba keratitis and granulomatous amoebic encephalitis among humans. Antimicrobial chemotherapy used against Acanthamoeba is toxic to human cells and show side effects as well. Infections due to Acanthamoeba also pose challenges towards currently used antimicrobial treatment including resistance and transformation of trophozoites to resistant cyst forms that can lead to recurrence of infection. Therapeutic agents targeting central nervous system infections caused by Acanthamoeba should be able to cross blood-brain barrier. Nanoparticles based drug delivery put forth an effective therapeutic method to overcome the limitations of currently used antimicrobial chemotherapy. In recent years, various researchers investigated the effectiveness of nanoparticles conjugated drug and/or naturally occurring plant compounds against both trophozoites and cyst form of Acanthamoeba. In the current review, a reasonable effort has been made to provide a comprehensive overview of various nanoparticles tested for their efficacy against Acanthamoeba. This review summarizes the noteworthy details of research performed to elucidate the effect of nanoparticles conjugated drugs against Acanthamoeba.


Assuntos
Acanthamoeba/efeitos dos fármacos , Amebicidas/administração & dosagem , Nanopartículas/administração & dosagem , Acanthamoeba/crescimento & desenvolvimento , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/parasitologia , Amebíase/tratamento farmacológico , Amebíase/mortalidade , Amebíase/parasitologia , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Biguanidas/administração & dosagem , Biguanidas/farmacologia , Biguanidas/uso terapêutico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/mortalidade , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Clorexidina/administração & dosagem , Clorexidina/farmacologia , Clorexidina/uso terapêutico , Sistemas de Liberação de Medicamentos , Imunocompetência , Hospedeiro Imunocomprometido , Encefalite Infecciosa/tratamento farmacológico , Encefalite Infecciosa/mortalidade , Encefalite Infecciosa/parasitologia , Nanopartículas/classificação , Nanopartículas/uso terapêutico , Trofozoítos/efeitos dos fármacos
3.
PLoS Negl Trop Dis ; 14(9): e0008353, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970675

RESUMO

Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 µM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.


Assuntos
Amebíase/tratamento farmacológico , Amebicidas/farmacologia , Reposicionamento de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Acanthamoeba/efeitos dos fármacos , Balamuthia mandrillaris/efeitos dos fármacos , Bases de Dados de Produtos Farmacêuticos , Naegleria fowleri/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas
4.
Exp Parasitol ; 218: 107979, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32866583

RESUMO

Balamuthia mandrillaris and Naegleria fowleri are free-living amoebae that can cause life-threatening infections involving the central nervous system. The high mortality rates of these infections demonstrate an urgent need for novel treatment options against the amoebae. Considering that indole and thiazole compounds possess wide range of antiparasitic properties, novel bisindole and thiazole derivatives were synthesized and evaluated against the amoebae. The antiamoebic properties of four synthetic compounds i.e., two new bisindoles (2-Bromo-4-(di (1H-indol-3-yl)methyl)phenol (denoted as A1) and 2-Bromo-4-(di (1H-indol-3-yl)methyl)-6-methoxyphenol (A2)) and two known thiazole (4-(3-Nitrophenyl)-2-(2-(pyridin-3-ylmethylene)hydrazinyl)thiazole (A3) and 4-(Biphenyl-4-yl)-2-(2-(1-(pyridin-4-yl)ethylidene)hydrazinyl)thiazole (A4)) were evaluated against B. mandrillaris and N. fowleri. The ability of silver nanoparticle (AgNPs) conjugation to enrich antiamoebic activities of the compounds was also investigated. The synthetic heterocyclic compounds demonstrated up to 53% and 69% antiamoebic activities against B. mandrillaris and N. fowleri respectively, while resulting in up to 57% and 68% amoebistatic activities, respectively. Antiamoebic activities of the compounds were enhanced by up to 71% and 51% against B. mandrillaris and N. fowleri respectively, after conjugation with AgNPs. These compounds exhibited potential antiamoebic effects against B. mandrillaris and N. fowleri and conjugation of synthetic heterocyclic compounds with AgNPs enhanced their activity against the amoebae.


Assuntos
Amebíase/tratamento farmacológico , Balamuthia mandrillaris/efeitos dos fármacos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Indóis/administração & dosagem , Naegleria fowleri/efeitos dos fármacos , Tiazóis/administração & dosagem , Amebíase/parasitologia , Amebicidas/administração & dosagem , Amebicidas/química , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Células HeLa , Humanos , Indóis/química , Concentração Inibidora 50 , Nanopartículas Metálicas , Tiazóis/química
5.
Parasitol Res ; 119(7): 2327-2335, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32476058

RESUMO

Acanthamoeba castellanii is a free-living amoeba which can cause a blinding keratitis and fatal granulomatous amoebic encephalitis. The treatment of Acanthamoeba infections is challenging due to formation of cyst. Quinazolinones are medicinally important scaffold against parasitic diseases. A library of nineteen new 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives was synthesized to evaluate their antiamoebic activity against Acanthamoeba castellanii. One-pot synthesis of 3-aryl-6,7-dimethoxyquinazolin-4(3H)-ones (1-19) was achieved by reaction of 2-amino-4,5-dimethoxybenzoic acid, trimethoxymethane, and different substituted anilines. These compounds were purified and characterized by standard chromatographic and spectroscopic techniques. Antiacanthamoebic activity of these compounds was determined by amoebicidal, encystation, excystation and host cell cytopathogenicity in vitro assays at concentrations of 50 and 100 µg/mL. The IC50 was found to be between 100 and 50 µg/mL for all the compounds except compound 5 which did not exhibit amoebicidal effects at these concentrations. Furthermore, lactate dehydrogenase assay was also performed to evaluate the in vitro cytotoxicity of these compounds against human keratinocyte (HaCaT) cells. The results revealed that eighteen out of nineteen derivatives of quinazolinones significantly decreased the viability of A. castellanii. Furthermore, eighteen out of nineteen tested compounds inhibited the encystation and excystation, as well as significantly reduced the A. castellanii-mediated cytopathogenicity against human cells. Interestingly, while tested against human normal cell line HaCaT keratinocytes, all compounds did not exhibit any overt cytotoxicity. Furthermore, a detailed structure-activity relationship is also studied to optimize the most potent hit from these synthetic compounds. This report presents several potential lead compounds belonging to 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives for drug discovery against infections caused by Acanthamoeba castellanii.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/química , Amebicidas/farmacologia , Quinazolinonas/química , Quinazolinonas/farmacologia , Acanthamoeba castellanii/crescimento & desenvolvimento , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Amebicidas/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Encistamento de Parasitas/efeitos dos fármacos , Quinazolinonas/síntese química , Relação Estrutura-Atividade
6.
J Fish Dis ; 43(6): 665-672, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32291787

RESUMO

Gill parasitic infections challenge farming of rainbow trout (Oncorhynchus mykiss, Walbaum) in freshwater facilities. Apart from flagellates (Ichthyobodo, (Pinto) and ciliates (Ichthyophthirius (Fouquet), Ambiphrya (Raabe), Apiosoma (Blanchard), Trichodinella (Sramek-Husek) and Trichodina (Ehrenberg)), we have shown that amoebae are prevalent in Danish trout farms. Gills were isolated from farmed rainbow trout in six fish farms (conventional and organic earth pond and recirculated systems) and placed on non-nutrient agar (NNA) moistened with modified Neff's amoeba saline (AS) (15°C). Gill amoebae from all examined fish colonized the agar and were identified based on morphological criteria showing species within the genera Trinema (Dujardin) (family Trinematidae), Vannella (Bovee) (family Vannellidae). In addition, hartmannellid amoebae were recorded. We established a monoculture of Vannella sp., confirmed the genus identity by PCR and sequencing and performed an in vitro determination of antiparasitic effects (dose-response studies) of various compounds including sodium chloride (NaCl), hydrogen peroxide, peracetic acid, formalin, aqueous garlic and oregano extracts and a Pseudomonas H6 surfactant. All amoebae were killed in concentrations of 16.90 mg/ml (garlic), 17.90 mg/ml (oregano), NaCl (7.5 mg/ml), hydrogen peroxide (100 µg/ml), peracetic acid (0.03 µg/ml), formaldehyde (25 µg/ml) and the Pseudomonas H6 surfactant (250 µg/ml).


Assuntos
Amebíase/veterinária , Antiparasitários/farmacologia , Oncorhynchus mykiss , Tubulinos/efeitos dos fármacos , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Animais , Relação Dose-Resposta a Droga , Doenças dos Peixes/tratamento farmacológico , Doenças dos Peixes/parasitologia , Água Doce , Brânquias/parasitologia , Técnicas In Vitro
7.
J Postgrad Med ; 66(2): 99-101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134005

RESUMO

Amebiasis caused by protozoa Entamoeba histolytica (EH) is the third leading parasitic cause of human mortality. Although amebiasis is endemic in India, only about 10% of the infected individuals manifest disease. Clinical spectrum of amebiasis ranges from asymptomatic colonization to amebic colitis to hemorrhagic and fulminant colitis. Factors causing an invasive infection are not completely understood. Pathogen virulence, host immunity, and ability of the pathogen to evade host immune response play vital role in determining the disease course. Host factors such as immunocompromised states may make an individual susceptible to develop symptomatic infection. Malignancies usually result in chronic debilitation which may make the individual prone to develop invasive amebiasis with rapid progression. We report two cases of invasive amebiasis which developed a fulminant course in the immediate postoperative period after abdominal surgeries for visceral malignancies.


Assuntos
Carcinoma/cirurgia , Colecistectomia/efeitos adversos , Disenteria Amebiana/diagnóstico , Entamoeba histolytica/isolamento & purificação , Neoplasias da Vesícula Biliar/cirurgia , Gastrectomia/efeitos adversos , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/parasitologia , Amebíase/diagnóstico , Amebíase/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Disenteria Amebiana/tratamento farmacológico , Feminino , Humanos , Masculino , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Resultado do Tratamento
8.
J Fish Dis ; 43(1): 39-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726482

RESUMO

Hydrogen peroxide (H2 O2 ) is a commonly used treatment for a range of parasitic diseases of marine finfish, including amoebic gill disease (AGD). While this treatment is partially effective at reducing parasite load, H2 O2 can have detrimental effects on the host under certain conditions. Treatment temperature and dose concentration are two factors that are known to influence the toxicity of H2 O2 ; however, their impact on the outcome of AGD treatment remains unclear. Here, we investigated the effects of treatment temperature (8, 12 or 16°C) and dose concentration (750, 1,000, 1,250 mg/L) on the efficacy of H2 O2 to treat AGD. We demonstrated that a 20-min bath treatment of H2 O2 at all doses reduced both parasite load and gross gill score significantly. Parasite load and gross gill score were lowest in the 1,000 mg/L treatment performed at 12°C. At the high dose and temperature combinations, H2 O2 caused moderate gill damage and a significant increase in the plasma concentration of electrolytes (sodium, chloride and potassium). Taken together, our study demonstrates that higher H2 O2 treatment temperatures can adversely affect the host and do not improve the effectiveness of the treatment.


Assuntos
Amebíase/veterinária , Antiprotozoários/uso terapêutico , Doenças dos Peixes/tratamento farmacológico , Peróxido de Hidrogênio/uso terapêutico , Salmo salar , Temperatura , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Animais , Relação Dose-Resposta a Droga , Feminino , Doenças dos Peixes/parasitologia , Brânquias/parasitologia
9.
Int J Med Microbiol ; 310(1): 151358, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31587966

RESUMO

Amoebiasis is a parasitic disease caused by Entamoeba histolytica (E. histolytica), an extracellular enteric protozoan. This infection mainly affects people from developing countries with limited hygiene conditions, where it is endemic. Infective cysts are transmitted by the fecal-oral route, excysting in the terminal ileum and producing invasive trophozoites (amoebae). E. histolytica mainly lives in the large intestine without causing symptoms; however, possibly as a result of so far unknown signals, the amoebae invade the mucosa and epithelium causing intestinal amoebiasis. E. histolytica possesses different mechanisms of pathogenicity for the adherence to the intestinal epithelium and for degrading extracellular matrix proteins, producing tissue lesions that progress to abscesses and a host acute inflammatory response. Much information has been obtained regarding the virulence factors, metabolism, mechanisms of pathogenicity, and the host immune response against this parasite; in addition, alternative treatments to metronidazole are continually emerging. An accesible and low-cost diagnostic method that can distinguish E. histolytica from the most nonpathogenic amoebae and an effective vaccine are necessary for protecting against amoebiasis. However, research about the disease and its prevention has been a challenge due to the relationship between E. histolytica and the host during the distinct stages of the disease is multifaceted. In this review, we analyze the interaction between the parasite, the human host, and the colon microbiota or pathogenic microorganisms, which together give rise to intestinal amoebiasis.


Assuntos
Amebíase/parasitologia , Países em Desenvolvimento , Disenteria Amebiana/parasitologia , Intestinos/parasitologia , Saúde Pública , Amebíase/tratamento farmacológico , Amebíase/epidemiologia , Animais , Antiprotozoários/uso terapêutico , Disenteria Amebiana/epidemiologia , Entamoeba histolytica/imunologia , Entamoeba histolytica/patogenicidade , Fezes/parasitologia , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno , Humanos , Intestinos/microbiologia , Metronidazol/uso terapêutico , Camundongos , Virulência
10.
Artigo em Inglês | MEDLINE | ID: mdl-31707263

RESUMO

The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.


Assuntos
Acanthamoeba/efeitos dos fármacos , Amebíase/tratamento farmacológico , Amebozoários/efeitos dos fármacos , Antiprotozoários/farmacologia , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Naegleria/efeitos dos fármacos , Amebíase/parasitologia , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Técnicas de Cultura de Células , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Meios de Cultura , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Concentração Inibidora 50 , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Plicamicina/farmacologia , Plicamicina/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
11.
Artigo em Inglês | MEDLINE | ID: mdl-31685474

RESUMO

Miltefosine is an alkylphosphocholine compound that is used primarily for treatment of leishmaniasis and demonstrates in vitro and in vivo antiamebic activity against Acanthamoeba species. Recommendations for treatment of amebic encephalitis generally include miltefosine therapy. Data indicate that treatment with an amebicidal concentration of at least 16 µg/ml of miltefosine is required for most Acanthamoeba species. Although there is a high level of mortality associated with amebic encephalitis, a paucity of data regarding miltefosine levels in plasma and cerebrospinal fluid in vivo exists in the literature. We found that despite aggressive dosing (oral miltefosine 50 mg every 6 h) and therapeutic plasma levels, the miltefosine concentration in cerebrospinal fluid was negligible in a patient with AIDS and Acanthamoeba encephalitis.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Amebíase/tratamento farmacológico , Amebicidas/sangue , Amebicidas/líquido cefalorraquidiano , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Encefalite Infecciosa/tratamento farmacológico , Fosforilcolina/análogos & derivados , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Acanthamoeba/efeitos dos fármacos , Acanthamoeba/isolamento & purificação , Adulto , Amebíase/sangue , Amebíase/líquido cefalorraquidiano , Amebicidas/administração & dosagem , Encéfalo/parasitologia , Infecções Protozoárias do Sistema Nervoso Central/sangue , Infecções Protozoárias do Sistema Nervoso Central/líquido cefalorraquidiano , Humanos , Encefalite Infecciosa/sangue , Encefalite Infecciosa/líquido cefalorraquidiano , Masculino , Fosforilcolina/administração & dosagem , Fosforilcolina/sangue , Fosforilcolina/líquido cefalorraquidiano
12.
Photodiagnosis Photodyn Ther ; 28: 166-171, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31499180

RESUMO

BACKGROUND: Microbial keratitis is a potential cause of corneal blindness. We investigated the amoebicidal efficacy of photodynamic antimicrobial therapy with a light-emitting diode as the light source and the cationic chlorin derivative TONS504 as the photosensitizer for the elimination of Acanthamoeba, a causative organism of corneal infection and blindness. Acanthamoeba keratitis remains a challenge to treat because of limited available treatments. METHODS: Acanthamoeba castellani 50370 was exposed to TONS504 at various concentrations (0, 1, or 10 mg/L for trophozoites; 0, 1, 10, or 20 mg/L for cysts), irradiated at various light energies (0, 10, or 30 J/cm2 for trophozoites; 0, 30, or 60 J/cm2 for cysts), and incubated at 26 °C for 3 h. Assessment of cell viability by trypan blue staining revealed that photodynamic antimicrobial therapy attenuated the survival of trophozoites and cysts dependent on TONS504 concentration and light energy. RESULTS: Photodynamic antimicrobial therapy with 10 mg/L TONS504 and 30 J/cm2 light energy suppressed trophozoite viability by 77%, and 20 mg/L TONS504 and 60 J/cm2 light energy attenuated cyst survival by 42%. Staining with fluorescein isothiocyanate-conjugated annexin V and ethidium homodimer III revealed photodynamic antimicrobial therapy induced apoptosis and necrosis in trophozoites dependent upon the intensity of treatment, whereas apoptosis was the predominant form of cell death in cysts. CONCLUSIONS: Photodynamic antimicrobial therapy with TONS504 warrants further investigation as a potential treatment modality for Acanthamoeba keratitis.


Assuntos
Amebíase/tratamento farmacológico , Ceratite/tratamento farmacológico , Ceratite/parasitologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Acanthamoeba castellanii/efeitos dos fármacos , Amebíase/parasitologia , Amebicidas/farmacologia , Animais , Oocistos/efeitos dos fármacos , Trofozoítos/efeitos dos fármacos
13.
Sci Rep ; 9(1): 11651, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406269

RESUMO

Recently, the search for novel therapeutic agents against Acanthamoeba species has been focused on the evaluation of natural resources. Among them, marine microorganisms have risen as a source of bioactive compounds with the advantage of the ability to obtain unlimited and constant amounts of the compounds in contrast to other natural sources such as plants. Furthermore, marine actinomycetes have recently been reported as highly rich in bioactive agents including salinosporamides, xiamycines, indolocarbazoles, naphtyridines, phenols, dilactones such as antimycines and macrolides among others. In this study, staurosporine (STS) was isolated from a strain of Streptomyces sanyensis and tested against Acanthamoeba to characterize the therapeutic potential of STS against this protozoan parasite. We have established that STS is active against both stages of the Acanthamoeba life cycle, by the activation of Programmed Cell Death via the mitochondrial pathway of the trophozoite. We have also established that STS has relatively low toxicity towards a macrophage cell line. However, previous studies have highlighted higher toxicity levels induced on other vertebrate cell lines and future research to lower these toxicity issues should be developed.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Organismos Aquáticos/química , Estaurosporina/farmacologia , Streptomyces/química , Acanthamoeba castellanii/citologia , Amebíase/tratamento farmacológico , Amebíase/parasitologia , Amebicidas/isolamento & purificação , Amebicidas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Humanos , Macrófagos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Estaurosporina/isolamento & purificação , Estaurosporina/uso terapêutico , Testes de Toxicidade Aguda , Trofozoítos/citologia , Trofozoítos/efeitos dos fármacos
14.
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
15.
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
16.
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
17.
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
18.
Clin Transplant ; 33(9): e13546, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30900295

RESUMO

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of tissue and blood protozoal infections in the pre- and post-transplant period. Significant new developments in the field have made it necessary to divide the previous single guideline published in 2013 into two sections, with the intestinal parasites separated from this guideline devoted to tissue and blood protozoa. The current update reflects the increased focus on donor screening and risk-based recipient monitoring for parasitic infections. Increased donor testing has led to new recommendations for recipient management of Toxoplasma gondii and Trypanosoma cruzi. Molecular diagnostics have impacted the field, with access to rapid diagnostic testing for malaria and polymerase chain reaction testing for Leishmania. Changes in Babesia treatment regimens in the immunocompromised host are outlined. The risk of donor transmission of free-living amebae infection is reviewed. Changing immigration patterns and the expansion of transplant medicine in developing countries has contributed to the recognition of parasitic infections as an important threat to transplant outcomes. Medications such as benznidazole and miltefosine are now available to US prescribers as access to treatment of tissue and blood protozoa is increasingly prioritized.


Assuntos
Antiprotozoários/uso terapêutico , Transplante de Órgãos/efeitos adversos , Guias de Prática Clínica como Assunto/normas , Infecções por Protozoários/diagnóstico , Infecções por Protozoários/tratamento farmacológico , Acanthamoeba/isolamento & purificação , Amebíase/diagnóstico , Amebíase/tratamento farmacológico , Amebíase/etiologia , Babesia/isolamento & purificação , Babesiose/diagnóstico , Babesiose/tratamento farmacológico , Babesiose/etiologia , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/etiologia , Doença de Chagas/diagnóstico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/etiologia , Humanos , Leishmania/isolamento & purificação , Leishmaniose/diagnóstico , Leishmaniose/tratamento farmacológico , Leishmaniose/etiologia , Naegleria/isolamento & purificação , Infecções por Protozoários/etiologia , Sociedades Médicas , Toxoplasma/isolamento & purificação , Toxoplasmose/diagnóstico , Toxoplasmose/tratamento farmacológico , Toxoplasmose/etiologia , Transplantados , Trypanosoma cruzi/isolamento & purificação
19.
Sci Rep ; 9(1): 3122, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816269

RESUMO

Herein, we report green synthesized nanoparticles based on stabilization by plant gums, loaded with citrus fruits flavonoids Hesperidin (HDN) and Naringin (NRG) as novel antimicrobial agents against brain-eating amoebae and multi-drug resistant bacteria. Nanoparticles were thoroughly characterized by using zetasizer, zeta potential, atomic force microscopy, ultravoilet-visible and Fourier transform-infrared spectroscopic techniques. The size of these spherical nanoparticles was found to be in the range of 100-225 nm. The antiamoebic effects of these green synthesized Silver and Gold nanoparticles loaded with HDN and NRG were tested against Acanthamoeba castellanii and Naegleria fowleri, while antibacterial effects were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and neuropathogenic Escherichia coli K1. Amoebicidal assays revealed that HDN loaded Silver nanoparticles stabilized by gum acacia (GA-AgNPs-HDN) quantitatively abolished amoeba viability by 100%, while NRG loaded Gold nanoparticles stabilized by gum tragacanth (GT-AuNPs-NRG) significantly reduced the viability of A. castellanii and N. fowleri at 50 µg per mL. Furthermore, these nanoparticles inhibited the encystation and excystation by more than 85%, as well as GA-AgNPs-HDN only completely obliterated amoeba-mediated host cells cytopathogenicity. Whereas, GA-AgNPs-HDN exhibited significant bactericidal effects against MRSA and E. coli K1 and reduced bacterial-mediated host cells cytotoxicity. Notably, when tested against human cells, these nanoparticles showed minimal (23%) cytotoxicity at even higher concentration of 100 µg per mL as compared to 50 µg per mL used for antimicrobial assays. Hence, these novel nanoparticles formulations hold potential as therapeutic agents against infections caused by brain-eating amoebae, as well as multi-drug resistant bacteria, and recommend a step forward in drug development.


Assuntos
Amebicidas/administração & dosagem , Antibacterianos/administração & dosagem , Flavanonas/administração & dosagem , Hesperidina/administração & dosagem , Nanopartículas/química , Gomas Vegetais/química , Acanthamoeba castellanii/efeitos dos fármacos , Amebíase/tratamento farmacológico , Amebicidas/química , Amebicidas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Citrus/química , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Flavanonas/química , Flavanonas/farmacologia , Química Verde , Goma Arábica/química , Hesperidina/química , Hesperidina/farmacologia , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico
20.
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
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