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1.
Sci Rep ; 12(1): 14926, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056060

RESUMO

Amoebae from the genus Acanthamoeba are important pathogens responsible for severe illnesses in humans such as Acanthamoeba keratitis and granulomatous amoebic encephalitis. In the last few decades, AK diagnoses have steadily increased. Most patients suffering from AK were contact lens users and the infection was related to poor hygiene. However, therapy is not yet well established, and treatments may last for several months due to resistance. Moreover, these treatments have been described to generate cytotoxicity. Therefore, there is an urgent need to develop new therapeutic strategies against AK. In this study, the amoebicidal activity of different generation cationic carbosilane dendrons derived with 4-phenylbutyric acid was demonstrated against Acanthamoeba polyphaga and Acanthamoeba griffini trophozoites and cysts. In addition, the combination of chlorhexidine digluconate and the most effective dendron (ArCO2G2(SNMe3I)4) showed an in vitro effect against Acanthamoeba trophozoites and cysts, reducing the minimal trophozoite amoebicidal concentration as well as concentrations with cysticidal activity.


Assuntos
Acanthamoeba castellanii , Acanthamoeba , Amebicidas , Cistos , Dendrímeros , Amebicidas/farmacologia , Animais , Cátions/farmacologia , Dendrímeros/farmacologia , Humanos , Fenilbutiratos , Silanos , Trofozoítos
2.
Mol Biochem Parasitol ; 250: 111492, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35714753

RESUMO

Acanthamoeba is opportunistic pathogens that cause vision-threatening Acanthamoeba keratitis (AK). Previous studies proposed the use of chloroquine (CQ) and 5-fluorouracil (5FU) as anti-Acanthamoeba agents. The objective of this study was to determine the benefit of using 5FU and CQ nanoparticles (NP) formulations against A. castellanii that belonging to the T4 genotype and evaluate their anti-Acanthamoebic characteristic. Triplicate batches of 5FU nanoparticles (5FU-NP) were synthesized by using a modified nanoprecipitation method, while CQ nanoparticles (CQ-NP) synthesized using a modified double emulsion method. The synthesized nanoparticles were subjected to biological assays to investigate their amoebicidal, amoebistatic, anti-encystation, and anti-excystation effects against A. castellanii, as well as cell cytotoxicity. Cytotoxicity assays were performed using human keratinocyte cells (HaCaT) to determine the effect of CQ and 5FU nanoformulations on host cells. 5FU-NP with a concentration of 60 µM showed significant inhibition to amoeba binding into human cell lines and remarkable prevention mainly during the encystation stage. Moreover, 5FU-NP resulted in less cytotoxicity and pathogenicity when compared with the free 5FU. On the other hand, CQ and CQ-NP, at the same concentration, showed poor inhibition to amoeba binding into human cells and insignificant prevention to encystation stage. Moderate human cells damage was resulted following their treatment with CQ and CQ-NP. In conclusion, 5FU may have the potential as an antiamoebic agent against Acanthamoeba spp. preferably as a nanoformulation to enhance its activity and reduce its cytoxicity.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Nanopartículas , Ceratite por Acanthamoeba/tratamento farmacológico , Acanthamoeba castellanii/genética , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Cloroquina/farmacologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos
3.
Mol Biochem Parasitol ; 250: 111493, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35753525

RESUMO

Acanthamoeba castellanii is a protist pathogen that can cause sight-threatening keratitis and a fatal infection of the central nervous system, known as granulomatous amoebic encephalitis. In this study, effects of five malonic acid and salicylic acid-based deep eutectic solvents (DES) on A. castellanii were investigated. These are salicylic acid-trioctylphosphine (DES 1), salicylic acid- trihexylamine (DES 2), salicylic acid-trioctylamine (DES 3), malonic acid-trioctylphosphine (DES 4) and malonic acid-trihexylamine (DES 5). The experiments were done by performing amoebicidal, encystment, excystment, cytopathogenicity, and cytotoxicity assays. At micromolar dosage, the solvents DES 2 and DES 3 displayed significant amoebicidal effects (P < 0.05), inhibited encystment and excystment, undermined the cell-mediated cytopathogenicity of A. castellanii, and also displayed minimal cytotoxicity to human cells. Conversely, the chemical components of these solvents: salicylic acid, trihexylamine, and trioctylamine showed minimal effects when tested individually. These results are very promising and to the best of our knowledge, are reported for the first time on the effects of deep eutectic solvents on amoebae. These results can be applied in the development of new formulations of novel contact lens disinfectants against Acanthamoeba castellanii.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Lentes de Contato , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/prevenção & controle , Amebicidas/química , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Soluções para Lentes de Contato/farmacologia , Soluções para Lentes de Contato/uso terapêutico , Solventes Eutéticos Profundos , Humanos , Ácido Salicílico/farmacologia , Ácido Salicílico/uso terapêutico
4.
Biomed Pharmacother ; 150: 113062, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35658232

RESUMO

The genus Acanthamoeba is characterized by being a group of ubiquitous and free-living amoebae that inhabit a variety of environments. Generally, human infections by this parasite are associated with Acanthamoeba keratitis, especially in contact lens wearers, and with chronic but fatal granulomatous amoebic meningoencephalitis. Current treatments used for eradication of amoeba from infection sites represent a challenge for pharmacotherapy, due to the lack of effective treatment and the amoebae highly resistant to anti-amoebic drugs. In this study, we describe the results of the assessment of the IC50 of 10 isobenzofuran-1(3H)-one derivatives (QOET) against four Acanthamoeba strains. The compounds QOET-3 and QOET-9 were the selected derivatives with the lowest IC50 in A. castellanii Neff trophozoites (73.71 ± 0.25 and 69.99 ± 15.32 µM, respectively). Interestingly, analysis of the compound effects on the cell apoptosis-like features showed that both active molecules triggered programmed cell death (PCD) in A. castellanii Neff. The results obtained in this study highlights that isobenzofuranone derivatives could represent an interesting source for developing novel antiamoebic drugs.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Ceratite por Acanthamoeba/parasitologia , Amebicidas/farmacologia , Animais , Morte Celular , Humanos , Trofozoítos
5.
Microbiol Spectr ; 10(3): e0007722, 2022 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-35467370

RESUMO

Traditional cysticidal assays for Acanthamoeba species revolve around treating cysts with compounds and manually observing the culture for evidence of excystation. This method is time-consuming, labor-intensive, and low throughput. We adapted and trained a YOLOv3 machine learning, object detection neural network to recognize Acanthamoeba castellanii trophozoites and cysts in microscopy images to develop an automated cysticidal assay. This trained neural network was used to count trophozoites in wells treated with compounds of interest to determine if a compound treatment was cysticidal. We validated this new assay with known cysticidal and noncysticidal compounds. In addition, we undertook a large-scale bioluminescence-based screen of 9,286 structurally unique marine microbial metabolite fractions against the trophozoites of A. castellanii and identified 29 trophocidal hits. These hits were then subjected to this machine learning-based automated cysticidal assay. One marine microbial metabolite fraction was identified as both trophocidal and cysticidal. IMPORTANCE The free-living Acanthamoeba can exist as a trophozoite or cyst and both stages can cause painful blinding keratitis. Infection recurrence occurs in approximately 10% of cases due to the lack of efficient drugs that can kill both trophozoites and cysts. Therefore, the discovery of therapeutics that are effective against both stages is a critical unmet need to avert blindness. Current efforts to identify new anti-Acanthamoeba compounds rely primarily upon assays that target the trophozoite stage of the parasite. We adapted and trained a machine learning, object detection neural network to recognize Acanthamoeba trophozoites and cysts in microscopy images. Our machine learning-based cysticidal assay improved throughput, demonstrated high specificity, and had an exquisite ability to identify noncysticidal compounds. We combined this cysticidal assay with our bioluminescence-based trophocidal assay to screen about 9,000 structurally unique marine microbial metabolites against A. castellanii. Our screen identified a marine metabolite that was both trophocidal and cysticidal.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/parasitologia , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Animais , Aprendizado de Máquina , Trofozoítos
6.
Acta Trop ; 231: 106440, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35378058

RESUMO

Acanthamoeba spp. are free living amoebae which can give rise to Acanthamoeba keratitis and granulomatous amoebic encephalitis. The surface of Acanthamoeba contains ergosterol which is an important target for drug development against eukaryotic microorganisms. A library of ten functionally diverse quinazolinone derivatives (Q1-Q10) were synthesised to assess their activity against Acanthamoeba castellanii T4. The in-vitro effectiveness of these quinazolinones were investigated against Acanthamoeba castellanii by amoebicidal, excystation, host cell cytopathogenicity, and NADPH-cytochrome c reductase assays. Furthermore, wound healing capability was assessed at different time durations. Maximum inhibition at 50 µg/mL was recorded for compounds Q5, Q6 and Q8, while the compound Q3 did not exhibit amoebicidal effects at tested concentrations. Moreover, LDH assay was conducted to assess the cytotoxicity of quinazolinones against HaCaT cell line. The results of wound healing assay revealed that all compounds are not cytotoxic and are likely to promote wound healing at 10 µg/mL. The excystation assays revealed that these compounds significantly inhibit the morphological transformation of A. castellanii. Compound Q3, Q7 and Q8 elevated the level of NADPH-cytochrome c reductase up to five folds. Sterol 14alpha-demethylase (CYP51) a reference enzyme in ergosterol pathway was used as a potential target for anti-amoebic drugs. In this study using i-Tasser, the protein structure of Acanthamoeba castellanii (AcCYP51) was developed in comparison with Naegleria fowleri protein (NfCYP51) structure. The sequence alignment of both proteins has shown 42.72% identity. Compounds Q1-Q10 were then molecularly docked with the predicted AcCYP51. Out of ten quinazolinones, three compounds (Q3, Q7 and Q8) showed good binding activity within 3 Å of TYR 114. The in-silico study confirmed that these compounds are the inhibitor of CYP51 target site. This report presents several potential lead compounds belonging to quinazolinone derivatives for drug discovery against Acanthamoeba infections.


Assuntos
Acanthamoeba castellanii , Amebíase , Amebicidas , Amebíase/tratamento farmacológico , Amebicidas/farmacologia , Citocromos c/metabolismo , Citocromos c/farmacologia , Citocromos c/uso terapêutico , Ergosterol/metabolismo , Humanos , NADP/metabolismo , NADP/farmacologia , NADP/uso terapêutico , Oxirredutases/metabolismo , Quinazolinonas/química , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
7.
Invest Ophthalmol Vis Sci ; 63(1): 11, 2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34994769

RESUMO

Purpose: To determine the amoebicidal activity of functionalized poly-epsilon-lysine hydrogels (pɛK+) against Acanthamoeba castellanii. Methods: A. castellanii trophozoites and cysts were grown in the presence of pɛK solution (0-2.17 mM), pɛK or pɛK+ hydrogels, or commercial hydrogel contact lens (CL) for 24 hours or 7 days in PBS or Peptone-Yeast-Glucose (PYG) media (nutrient-deplete or nutrient-replete cultures, respectively). Toxicity was determined using propidium iodide and imaged using fluorescence microscopy. Ex vivo porcine corneas were inoculated with A. castellanii trophozoites ± pɛK, pɛK+ hydrogels or commercial hydrogel CL for 7 days. Corneal infection was assessed by periodic acid-Schiff staining and histologic analysis. Regrowth of A. castellanii from hydrogel lenses and corneal discs at 7 days was assessed using microscopy and enumeration. Results: The toxicity of pɛK+ hydrogels resulted in the death of 98.52% or 83.31% of the trophozoites at 24 hours or 7 days, respectively. The toxicity of pɛK+ hydrogels resulted in the death of 70.59% or 82.32% of the cysts in PBS at 24 hours or 7 days, respectively. Cysts exposed to pɛK+ hydrogels in PYG medium resulted in 75.37% and 87.14% death at 24 hours and 7 days. Ex vivo corneas infected with trophozoites and incubated with pɛK+ hydrogels showed the absence of A. castellanii in the stroma, with no regrowth from corneas or pɛK+ hydrogel, compared with infected-only corneas and those incubated in presence of commercial hydrogel CL. Conclusions: pɛK+ hydrogels demonstrated pronounced amoebicidal and cysticidal activity against A. castellanii. pɛK+ hydrogels have the potential for use as CLs that could minimize the risk of CL-associated Acanthamoeba keratitis.


Assuntos
Ceratite por Acanthamoeba/tratamento farmacológico , Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Córnea/parasitologia , Infecções Oculares Parasitárias/tratamento farmacológico , Hidrogéis/farmacologia , Polilisina/farmacologia , Ceratite por Acanthamoeba/parasitologia , Amebicidas/toxicidade , Animais , Células Cultivadas , Soluções para Lentes de Contato/farmacologia , Modelos Animais de Doenças , Epitélio Corneano/efeitos dos fármacos , Infecções Oculares Parasitárias/parasitologia , Humanos , Hidrogéis/toxicidade , Microscopia de Fluorescência , Polilisina/toxicidade , Suínos , Trofozoítos/efeitos dos fármacos
8.
ACS Infect Dis ; 8(2): 271-279, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-34994538

RESUMO

Acanthamoeba is a ubiquitous and free-living protozoan pathogen responsible for causing Acanthamoeba keratitis (AK), a severe corneal infection inflicting immense pain that can result in permanent blindness. A drug-based treatment of AK has remained arduous because Acanthamoeba trophozoites undergo encystment to become highly drug-resistant cysts upon exposure to harsh environmental conditions such as amoebicidal agents (e.g., polyhexanide, chloroquine, and chlorohexidine). As such, drugs that block the Acanthamoeba encystation process could result in a successful AK treatment. Histone deacetylase inhibitors (HDACi) have recently emerged as novel therapeutic options for treating various protozoan and parasitic diseases. Here, we investigated whether novel HDACi suppress the proliferation and encystation of Acanthamoeba. Synthetic class II HDACi FFK29 (IIa selective) and MPK576 (IIb selective) dose-dependently decreased the viability of Acanthamoeba trophozoites. While these HDACi demonstrated a negligible effect on the viability of mature cysts, Acanthamoeba encystation was significantly inhibited by these HDACi. Apoptosis was slightly increased in trophozoites after a treatment with these HDACi, whereas cysts were unaffected by the HDACi exposure. The viability of human corneal cells was not affected by HDACi concentrations up to 10 µmol/L. In conclusion, these synthetic HDACi demonstrated potent amoebicidal effects and inhibited the growth and encystation of Acanthamoeba, thus highlighting their enormous potential for further development.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/parasitologia , Amebicidas/farmacologia , Animais , Inibidores de Histona Desacetilases/farmacologia , Humanos , Trofozoítos
9.
Mol Biochem Parasitol ; 247: 111430, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34813865

RESUMO

In this study, curcumin-nanoformulations were tested for anti-Acanthamoebic properties. Curcumin-loaded nanovesicles were synthesized, followed by characterization with Fourier transform infrared spectroscopy, ultraviolet-visible spectrophotometry, and atomic force microscopy. Using amoebicidal assay, the effects of curcumin-nanoformulations were investigated against A. castellanii belonging to the T4 genotype. To determine the effects of curcumin-nanoformulations on host cells, cytotoxicity assays were performed using human keratinocyte cells (HaCat). The results revealed that nanovesicles formulation of curcumin enhanced the anti-Acanthamoebic effects of curcumin as compared with curcumin alone. The viability decreased with increasing concentration of curcumin and/or lipid-based carrier (Noisome) (FCBR18) in a dose-dependent manner. Curcumin and curcumin-loaded nanovesicles exhibited minimal cytotoxic effects against human cells in all tested concentrations. Both concentrations of FCBR18 proved effective in inhibiting amoebae excystation. In contrast, curcumin alone showed insignificant effects against amoebae excystation. Taken together, these findings clearly showed that curcumin-loaded nanovesicles show enhanced anti-Acanthamoebic efficacy without harming human cells, and these nanotherapeutics may hold promise in the development of new formulations of anti-Acanthamoebic agents.


Assuntos
Acanthamoeba castellanii , Amebicidas , Curcumina , Acanthamoeba castellanii/genética , Amebicidas/química , Amebicidas/farmacologia , Curcumina/farmacologia , Humanos , Microscopia de Força Atômica
10.
Acta Trop ; 224: 106144, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34562424

RESUMO

Acanthamoeba spp. are the causative agents of a sight-threatening infection of the cornea known as Acanthamoeba keratitis (AK). Amphotericin B - deoxycholate (AB) is used in the treatment of infectious keratitis, however, its topical administration has side effects as blepharitis, iritis, and painful instillation. In this context, the preheating of AB can decrease its toxicity by the formation of super aggregates (hAB). hAB associated with a thermoreversible in situ gelling ophthalmic system is a promising option due to the latter biocompatibility, low toxicity, and high residence time on the ocular surface. Our objective was to develop a topical ocular formulation of hAB for the treatment of AK. After heating at 70°C for 20 min, hAB was incorporated into a thermoreversible gelling system. The amebicidal activity of AB and hAB was evaluated against trophozoites and cysts of A. castellanii (ATCC 50492) and a regional clinical isolate (IC01). The results showed that the preheating of AB did not change the pharmacological action of the drug, with the amebicidal effect of AB and hAB under trophozoites and cysts of Acanthamoeba spp. The thermoreversible system remained stable, allowing the increase of drug retention time. For assessment of cytotoxicity, HUVEC (ATCC® CRL-1730) cells were challenged with AB and hAB for 48h. Cell viability was assessed, and hAB did not show cytotoxicity for HUVEC cells. As far as we know this was the first study that showed the preheated AB associated with a thermoreversible in situ gelling ophthalmic system as a promising system for topical ocular topical administration of hAB for AK therapy.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Amebicidas/farmacologia , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Animais , Trofozoítos
11.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208750

RESUMO

Entamoeba histolytica (protozoan; family Endomoebidae) is the cause of amoebiasis, a disease related to high morbidity and mortality. Nowadays, this illness is considered a significant public health issue in developing countries. In addition, parasite resistance to conventional medicinal treatment has increased in recent years. Traditional medicine around the world represents a valuable source of alternative treatment for many parasite diseases. In a previous paper, we communicated about the antiprotozoal activity in vitro of the methanolic (MeOH) extract of Ruta chalepensis (Rutaceae) against E. histolytica. The plant is extensively employed in Mexican traditional medicine. The following workup of the MeOH extract of R. chalepensis afforded the furocoumarins rutamarin (1) and chalepin (2), which showed high antiprotozoal activity on Entamoeba histolytica trophozoites employing in vitro tests (IC50 values of 6.52 and 28.95 µg/mL, respectively). Therefore, we offer a full scientific report about the bioguided isolation and the amebicide activity of chalepin and rutamarin.


Assuntos
Furocumarinas/isolamento & purificação , Ruta/metabolismo , Amebicidas/isolamento & purificação , Amebicidas/farmacologia , Antiprotozoários/farmacologia , Benzopiranos/metabolismo , Entamoeba histolytica/efeitos dos fármacos , Entamoeba histolytica/patogenicidade , Furocumarinas/farmacologia , Concentração Inibidora 50 , Medicina Tradicional , México , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia
12.
Acta Trop ; 220: 105981, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34048787

RESUMO

Acanthamoeba species are free-living amoebae isolated from many ecological areas such as swimming pools, dams, lakes, soil, and air filters. These amoebae are usually causing granulomatous amebic encephalitis and amebic keratitis in immunosuppressive individuals. In this study, the reproductive potential and morphological changes determined of Acanthamoeba castellanii trophozoite and cyst forms exposed to three different active substances derived from benzothiazole. Furthermore, the cytotoxic potential of these active substances determined by XTT analysis. In the study, axenic cultures prepared for Acanthamoeba castellanii cyst and trophozoite forms and parasite exposed to different concentrations of active substances. Cell counts of parasite cultures were performed at the 30 minutes, 1st, 6th, 12th, 24th, and 48th hour periods. As a result of the study, the reproductive potential suppressive effects of all three substances on Acanthamoeba castellanii trophozoites and cysts were determined. The most effective of these substances was 2-Amino-6(trifluoromethoxy)-benzothiazole. In the first three concentrations of this substance (0.1%, 0.05%, 0.025%), no determined trophozoite and cysts at the end of twenty four. Due to its strong ameobicidal effect, it is thought that 2-Amino-6(trifluoromethoxy)-benzothiazole may be a new therapeutic agent in diseases caused by acanthamoeba parasites by supporting this study with animal experiments.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Acanthamoeba castellanii/crescimento & desenvolvimento , Amebíase/tratamento farmacológico , Benzotiazóis/farmacologia , Amebicidas/farmacologia , Trofozoítos/efeitos dos fármacos
13.
Parasitology ; 148(9): 1074-1082, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33966667

RESUMO

Cassia angustifolia Vahl. plant is used for many therapeutic purposes, for example, in people with constipation, skin diseases, including helminthic and parasitic infections. In our study, we demonstrated an amoebicidal activity of C. angustifolia extract against Acanthamoeba triangularis trophozoite at a micromolar level. Scanning electron microscopy (SEM) images displayed morphological changes in the Acanthamoeba trophozoite, which included the formation of pores in cell membrane and the membrane rupture. In addition to the amoebicidal activity, effects of the extract on surviving trophozoites were observed, which included cyst formation and vacuolization by a microscope and transcriptional expression of Acanthamoeba autophagy in response to the stress by quantitative polymerase chain reaction. Our data showed that the surviving trophozoites were not transformed into cysts and the trophozoite number with enlarged vacuole was not significantly different from that of untreated control. Molecular analysis data demonstrated that the mRNA expression of AcATG genes was slightly changed. Interestingly, AcATG16 decreased significantly at 12 h post treatment, which may indicate a transcriptional regulation by the extract or a balance of intracellular signalling pathways in response to the stress, whereas AcATG3 and AcATG8b remained unchanged. Altogether, these data reveal the anti-Acanthamoeba activity of C. angustifolia extract and the autophagic response in the surviving trophozoites under the plant extract pressure, along with data on the formation of cysts. These represent a promising plant for future drug development. However, further isolation and purification of an active compound and cytotoxicity against human cells are needed, including a study on the autophagic response at the protein level.


Assuntos
Acanthamoeba castellanii/efeitos dos fármacos , Amebicidas/farmacologia , Genes de Protozoários/efeitos dos fármacos , Extratos Vegetais/farmacologia , Senna (Planta)/química , Transcrição Genética/efeitos dos fármacos , Acanthamoeba castellanii/genética , Extratos Vegetais/química
14.
Artigo em Inglês | MEDLINE | ID: mdl-33895610

RESUMO

The main corneal infections reported worldwide are caused by bacteria and viruses but, recently, the number of Acanthamoeba keratitis (AK) cases has increased. Acanthamoeba genus is an opportunistic free living protozoa widely distributed in environmental and clinical sources, with two life-cycle stages: the trophozoite and the cyst. AK presents as primary symptoms eye redness, epithelial defects, photophobia and intense pain. An early diagnosis and an effective treatment are crucial to avoid blindness or eye removal but, so far, there is no established treatment to this corneal infection. Diverse research studies have reported the efficacy of commercialized eye drops and ophthalmic solutions against the two life cycle stages of Acanthamoeba strains, that usually present preservatives such as Propylene Glycol of Benzalkonium chloride (BAK). These compounds present toxic effects in corneal cells, favouring the inflammatory response in the so sensitive eye tissue. In the present work we have evaluated the efficacy of nine proprietary ophthalmic solutions with and without preservatives (ASDA Dry Eyes Eyedrops, Miren®, ODM5®, Ectodol®, Systane® Complete, Ocudox®, Matrix Ocular®, Alins® and Coqun®) against the two life cycle stages of three Acanthamoeba strains. Our work has demonstrated the high anti-Acanthamoeba activity of Matrix Ocular®, which induces the programmed cell death mechanisms in Acanthamoeba spp. trophozoites. The high efficacy and the absence of ocular toxic effects of Matrix Ocular®, evidences the use of the Arabinogalactan derivatives as a new source of anti-AK compounds.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Galactanos , Humanos , Soluções Oftálmicas/uso terapêutico
15.
Expert Rev Anti Infect Ther ; 19(11): 1427-1441, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33929276

RESUMO

Introduction: Acanthamoeba encompasses several species of free-living ameba encountered commonly throughout the environment. Unfortunately, these species of ameba can cause opportunistic infections that result in Acanthamoeba keratitis, granulomatous amebic encephalitis, and occasionally systemic infection.Areas covered: This review discusses relevant literature found through PubMed and Google scholar published as of January 2021. The review summarizes current common Acanthamoeba keratitis treatments, drug discovery methodologies available for screening potential anti-Acanthamoeba compounds, and the anti-Acanthamoeba activity of various azole antifungal agents.Expert opinion: While several biguanide and diamidine antimicrobial agents are available to clinicians to effectively treat Acanthamoeba keratitis, no singular treatment can effectively treat every Acanthamoeba keratitis case.Efforts to identify new anti-Acanthamoeba agents include trophozoite cell viability assays, which are amenable to high-throughput screening. Cysticidal assays remain largely manual and would benefit from further automation development. Additionally, the existing literature on the effectiveness of various azole antifungal agents for treating Acanthamoeba keratitis is incomplete or contradictory, suggesting the need for a systematic review of all azoles against different pathogenic Acanthamoeba strains.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Azóis/farmacologia , Azóis/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos
16.
Int J Parasitol Drugs Drug Resist ; 15: 144-151, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33684885

RESUMO

The validation of anti-Acanthamoeba activity of commercial eye drops has gained a great interest recently and a growing number of commercials eye drop were evaluated for their aptitude to inhibit Acanthamoeba as a second pharmacological effect. In the present study, three different eye drops, commercializing in Spain, including TobraDex, Cusimolol and Colircusi antiedema have been tested in vitro against trophozoites and cysts stage of the facultative pathogen Acanthamoeba. The alamarBlue™ method was used to evaluate both trophocidal and cysticidal properties. The most active eye drops were tested for their impact on some programmed cell death features. We found out that the cells inhibition was strain and eye drop dependent, and 5% eye drop was able to eliminate both trophozoite and cyst stage of Acanthamoeba spp. A treatment of 24 h with 5% of TobraDex or Cusimolol was able to show DNA condensation, collapse in the mitochondrial membrane potential and reduction of the ATP level production in Acanthamoeba. We could assume that the present eye drops could induce programed cell death like process in Acanthamoeba via mitochondrial pathway.


Assuntos
Acanthamoeba , Amebicidas , Soluções Oftálmicas , Acanthamoeba/efeitos dos fármacos , Amebicidas/farmacologia , Amebicidas/uso terapêutico , Soluções Oftálmicas/farmacologia , Soluções Oftálmicas/uso terapêutico , Trofozoítos
17.
Clin Transl Sci ; 14(3): 791-805, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33650319

RESUMO

Free-living amoebae (FLAs) are protozoa developing autonomously in diverse natural or artificial environments. The FLAs Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri represent a risk for human health as they can become pathogenic and cause severe cerebral infections, named granulomatous amoebic encephalitis (GAE), Balamuthia amoebic encephalitis (BAE), and primary amoebic meningoencephalitis (PAM), respectively. Additionally, Acanthamoeba sp. can also rarely disseminate to diverse organs, such as the skin, sinuses, or bones, and cause extracerebral disseminated acanthamebiasis (EDA). No consensus treatment has been established for cerebral FLA infections or EDA. The therapy of cerebral and disseminated FLA infections often empirically associates a large diversity of drugs, all exhibiting a high toxicity. Nevertheless, these pathologies lead to a high mortality, above 90% of the cases, even in the presence of a treatment. In the present work, a total of 474 clinical cases of FLA infections gathered from the literature allowed to determine the frequency of usage, as well as the efficacy of the main drugs and drug combinations used in the treatment of these pathologies. The efficacy of drug usage was determined based on the survival rate after drug administration. The most efficient drugs, drug combinations, and their mechanism of action were discussed in regard to the present recommendations for the treatment of GAE, EDA, BAE, and PAM. At the end, this review aims to provide a useful tool for physicians in their choice to optimize the treatment of FLA infections.


Assuntos
Amebíase/tratamento farmacológico , Amebicidas/uso terapêutico , Amoeba/efeitos dos fármacos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Amebíase/mortalidade , Amebíase/parasitologia , Amebicidas/farmacologia , Amoeba/patogenicidade , Infecções Protozoárias do Sistema Nervoso Central/mortalidade , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Quimioterapia Combinada/métodos , Humanos , Taxa de Sobrevida , Resultado do Tratamento
18.
Molecules ; 26(4)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572129

RESUMO

Genetically uniform plant material, derived from Lychnis flos-cuculi propagated in vitro, was used for the isolation of 20-hydroxyecdysone and polypodine B and subjected to an evaluation of the antifungal and antiamoebic activity. The activity of 80% aqueous methanolic extracts, their fractions, and isolated ecdysteroids were studied against pathogenic Acanthamoeba castellani. Additionally, a Microtox® acute toxicity assay was performed. It was found that an 80% methanolic fraction of root extract exerts the most potent amoebicidal activity at IC50 of 0.06 mg/mL at the 3rd day of treatment. Both ecdysteroids show comparable activity at IC50 of 0.07 mg/mL. The acute toxicity of 80% fractions at similar concentrations is significantly higher than that of 40% fractions. Crude extracts exhibited moderate antifungal activity, with a minimum inhibitory concentration (MIC) within the range of 1.25-2.5 mg/mL. To the best of our knowledge, the present report is the first to show the biological activity of L. flos-cuculi in terms of the antifungal and antiamoebic activities and acute toxicity. It is also the first isolation of the main ecdysteroids from L. flos-cuculi micropropagated, ecdysteroid-rich plant material.


Assuntos
Amebicidas/farmacologia , Antifúngicos/farmacologia , Ecdisteroides/isolamento & purificação , Ecdisteroides/farmacologia , Fungos/efeitos dos fármacos , Lychnis/química , Extratos Vegetais/farmacologia , Amebicidas/isolamento & purificação , Antifúngicos/isolamento & purificação
19.
Acta Trop ; 216: 105830, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33465352

RESUMO

Amoebae of the genus Acanthamoeba are worldwide distributed causative agents of serious human infections such as granulomatous amoebic encephalitis (GAE) and Acanthamoeba keratitis (AK). To date, treatment of these infections is non-uniform and frequently unsuccessful. Recently, the phosphonium salts were studied for their high levels of antimicrobial activity. This work was aimed to investigate the cytotoxic effect of metronidazole and two phosphonium salts (PS1, PS2) on two clinical Acanthamoeba isolates. The isolates showed distinctly higher susceptibility to both phosphonium salts than to metronidazole. The highest susceptibility was noted to PS1 after 48 h of incubation. Metronidazole derivate PS2 showed higher susceptibility than metronidazole. The values of EC50 of PS2 were approximately twenty times lower than EC50 of metronidazole for Acanthamoeba lugdunensis strain and sixteen times lower for Acanthamoeba quina strain after 48 h. Although the therapeutic effect of metronidazole in Acanthamoeba infections is usually insufficient, its derivatisation can result in a significantly higher amoebicidal effect. Cytomorphological changes of trophozoites after exposure to tested compounds included rounding up of the cells, damage of membrane integrity, presence of pathological protrusions, elongation of the cells or pseudocyst-like stages. Obtained results indicate possible therapeutic potential of studied phosphonium salts.


Assuntos
Acanthamoeba/efeitos dos fármacos , Amebicidas/farmacologia , Metronidazol/análogos & derivados , Metronidazol/farmacologia , Trofozoítos/efeitos dos fármacos , Acanthamoeba/genética , Animais , Genótipo , Humanos
20.
Arch Pharm (Weinheim) ; 354(2): e2000263, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33017058

RESUMO

Entamoeba histolytica is a cosmopolitan protozoan parasite that can produce infections in the intestine and some organs (liver, lungs, and brain), with worldwide prevalence. There are treatments against E. histolytica (antiparasitics), but as the drugs used in these treatments have presented some type of resistance and/or side effects, there are cases with complications of this disease. Therefore, it is necessary to develop new drugs aimed at a specific therapeutic target against this parasite. Here, we used the compound 5,5'-[(4-nitrophenyl)methylene]bis(6-hydroxy-2-mercapto-3-methyl-4(3H)-pyrimidinone) in the patenting process (called D4). D4 has a reported specific use against a glycolytic enzyme, the triosephosphate isomerase of Trichomonas vaginalis (TvTIM). We determined that D4 has an amoebicidal effect in in vitro cultures, with an IC50 value of 18.5 µM, and we proposed a specific site of interaction (Lys77, His110, Gln115, and Glu118) in the triosephosphate isomerase of E. histolytica (EhTIM). Furthermore, compound D4 has favorable experimental and theoretical toxicity results. Therefore, D4 should be further investigated as a potential drug against E. histolytica.


Assuntos
Amebicidas/farmacologia , Entamoeba histolytica/efeitos dos fármacos , Amebicidas/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
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