RESUMO
Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate these agents are potent inhibitors of N. fowleri ENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50 = 0.14 ± 0.04 µM) that was toxic to trophozoites (EC50 = 0.21 ± 0.02 µM) while the reported CC50 was >300 µM. Molecular docking simulation revealed that HEX binds strongly to the active site of NfENO with a binding affinity of -8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of NfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the end of the one-week observation, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. However, intranasal HEX delivery was not curative as brains of six of the eight survivors were positive for amoebae. These findings suggest that HEX requires further evaluation to develop as a lead for treatment of PAM.
Assuntos
Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Fosfopiruvato Hidratase , Animais , Naegleria fowleri/efeitos dos fármacos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Fosfopiruvato Hidratase/metabolismo , Fosfopiruvato Hidratase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Camundongos , Ratos , Humanos , Simulação de Acoplamento MolecularAssuntos
Amebíase , Humanos , Amebíase/tratamento farmacológico , Amebíase/enfermagem , Amebíase/diagnóstico , Meningoencefalite/tratamento farmacológico , Masculino , Infecções Protozoárias do Sistema Nervoso Central/enfermagem , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológicoRESUMO
Naegleria fowleri invades the brain and causes a fatal primary amoebic meningoencephalitis (PAM). Despite its high mortality rate of approximately 97%, an effective therapeutic drug for PAM has not been developed. Approaches with miltefosine, amphotericin B, and other antimicrobials have been clinically attempted to treat PAM, but their therapeutic efficacy remains unclear. The development of an effective and safe therapeutic drug for PAM is urgently needed. In this study, we investigated the anti-amoebic activity of Pinus densiflora leaf extract (PLE) against N. fowleri. PLE induced significant morphological changes in N. fowleri trophozoites, resulting in the death of the amoeba. The IC50 of PLE on N. fowleri was 62.3±0.95 µg/ml. Alternatively, PLE did not significantly affect the viability of the rat glial cell line C6. Transcriptome analysis revealed differentially expressed genes (DEGs) between PLE-treated and non-treated amoebae. A total of 5,846 DEGs were identified, of which 2,189 were upregulated, and 3,657 were downregulated in the PLE-treated amoebae. The DEGs were categorized into biological process (1,742 genes), cellular component (1,237 genes), and molecular function (846 genes) based on the gene ontology analysis, indicating that PLE may have dramatically altered the biological and cellular functions of the amoeba and contributed to their death. These results suggest that PLE has anti-N. fowleri activity and may be considered as a potential candidate for the development of therapeutic drugs for PAM. It may also be used as a supplement compound to enhance the therapeutic efficacy of drugs currently used to treat PAM.
Assuntos
Naegleria fowleri , Pinus , Extratos Vegetais , Folhas de Planta , Naegleria fowleri/efeitos dos fármacos , Naegleria fowleri/genética , Extratos Vegetais/farmacologia , Pinus/química , Folhas de Planta/química , Animais , Ratos , Antiprotozoários/farmacologia , Linhagem Celular , Trofozoítos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/parasitologia , Encéfalo/metabolismo , Encéfalo/patologia , Perfilação da Expressão Gênica , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Concentração Inibidora 50 , Sobrevivência Celular/efeitos dos fármacosRESUMO
Naegleria fowleri, known as the brain-eating amoeba, is the pathogen that causes the primary amoebic meningoencephalitis (PAM), a severe neurodegenerative disease with a fatality rate exceeding 95%. Moreover, PAM cases commonly involved previous activities in warm freshwater bodies that allow amoebae-containing water through the nasal passages. Hence, awareness among healthcare professionals and the general public are the key to contribute to a higher and faster number of diagnoses worldwide. Current treatment options for PAM, such as amphotericin B and miltefosine, are limited by potential cytotoxic effects. In this context, the repurposing of existing compounds has emerged as a promising strategy. In this study, the evaluation of the COVID Box which contains 160 compounds demonstrated significant in vitro amoebicidal activity against two type strains of N. fowleri. From these compounds, terconazole, clemastine, ABT-239 and PD-144418 showed a higher selectivity against the parasite compared to the remaining products. In addition, programmed cell death assays were conducted with these four compounds, unveiling compatible metabolic events in treated amoebae. These compounds exhibited chromatin condensation and alterations in cell membrane permeability, indicating their potential to induce programmed cell death. Assessment of mitochondrial membrane potential disruption and a significant reduction in ATP production emphasized the impact of these compounds on the mitochondria, with the identification of increased ROS production underscoring their potential as effective treatment options. This study emphasizes the potential of the mentioned COVID Box compounds against N. fowleri, providing a path for enhanced PAM therapies.
Assuntos
Infecções Protozoárias do Sistema Nervoso Central , Reposicionamento de Medicamentos , Naegleria fowleri , Naegleria fowleri/efeitos dos fármacos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Humanos , Amebicidas/farmacologia , Amebicidas/uso terapêutico , COVID-19RESUMO
Primary amoebic meningoencephalitis (PAM) is a rare and fulminant neurodegenerative disease caused by the free-living amoeba Naegleria fowleri. Currently, there is a lack of standardized protocols for therapeutic action. In response to the critical need for effective therapeutic agents, we explored the Global Health Priority Box, a collection of 240 compounds provided by the Medicines for Malaria Venture (MMV). From this pool, flucofuron emerged as a promising candidate, exhibiting high efficacy against trophozoites of both N. fowleri strains (ATCC 30808 IC50 : 2.58 ± 0.64 µM and ATCC 30215 IC50: 2.47 ± 0.38 µM), being even active against the resistant cyst stage (IC50: 0.88 ± 0.07 µM). Moreover, flucofuron induced diverse metabolic events that suggest the triggering of apoptotic cell death. This study highlights the potential of repurposing medications for treating challenging diseases, such as PAM.
Assuntos
Naegleria fowleri , Naegleria fowleri/efeitos dos fármacos , Humanos , Trofozoítos/efeitos dos fármacos , Antiprotozoários/farmacologia , Reposicionamento de Medicamentos , Apoptose/efeitos dos fármacos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Amebíase/tratamento farmacológico , Amebíase/parasitologiaRESUMO
Primary amebic meningoencephalitis caused by Naegleria fowleri is a rare but nearly always fatal parasitic infection of the brain. Globally, few survivors have been reported, and the disease has no specific treatment. We report a confirmed case in Pakistan in a 22-year-old man who survived after aggressive therapy.
Assuntos
Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Masculino , Humanos , Adulto Jovem , Adulto , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Encéfalo , Paquistão/epidemiologia , SobreviventesRESUMO
Primary amebic meningoencephalitis (PAM) is a necrotizing and hemorrhagic inflammation of the brain and meninges caused by Naegleria fowleri, a free-living thermophilic ameba of freshwater systems. PAM remains a neglected disease that disproportionately affects children in tropical and subtropical climates, with an estimated mortality rate of 95-98%. Due to anthropogenic climate change, the average temperature in the USA has increased by 0.72 to 1.06 °C in the last century, promoting the poleward spread of N. fowleri. PAM is often misdiagnosed as bacterial meningitis or viral encephalitis, which shortens the window for potentially life-saving treatment. Diagnosis relies on the patient's history of freshwater exposure and the physician's high index of suspicion, supported by cerebrospinal fluid studies. While no experimental trials have been conducted to assess the relative efficacy of treatment regimens, anti-amebic therapy with adjunctive neuroprotection is standard treatment in the USA. We performed a literature review and identified five patients from North America between 1962 and 2022 who survived PAM with various degrees of sequelae.
Assuntos
Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Criança , Humanos , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Encéfalo , Mudança Climática , Progressão da DoençaRESUMO
Acanthamoeba spp. are rare etiological agents of meningoencephalitis with high mortality. We present three cases of Acanthamoeba meningoencephalitis in immunocompetent individuals from Eastern India. The first patient presented with fever and headache; the second with headache, visual disturbance, and squint; and the third presented in a drowsy state. The cases presented on March 3, 18, and 21, 2023 respectively. The first two patients had concomitant tubercular meningitis for which they received antitubercular therapy and steroid. Their cerebrospinal fluid showed slight lymphocytic pleocytosis and increased protein. The diagnosis was done by microscopy, culture, and polymerase chain reaction. They received a combination therapy comprising rifampicin, fluconazole, and trimethoprim-sulfamethoxazole. The first patient additionally received miltefosine. She responded well to therapy and survived, but the other two patients died despite intensive care. Detection of three cases within a period of 1 month from Eastern India is unusual. It is imperative to sensitize healthcare providers about Acanthamoeba meningoencephalitis to facilitate timely diagnosis and treatment of the disease.
Assuntos
Acanthamoeba , Amebíase , Infecções Protozoárias do Sistema Nervoso Central , Meningoencefalite , Humanos , Feminino , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Amebíase/diagnóstico , Amebíase/tratamento farmacológico , Meningoencefalite/diagnóstico , Meningoencefalite/tratamento farmacológico , Índia , CefaleiaRESUMO
Primary amoebic meningoencephalitis (PAM) is a rapidly progressing central nervous system (CNS) infection caused by Naegleria fowleri, a free-living amoeba found in warm freshwater. The disease progression is very rapid, and the outcome is nearly always fatal. We aim to describe the disease course in patients admitted with PAM in a tertiary care center in Karachi, Pakistan between the periods of 2010 to 2021. A total of 39 patients were included in the study, 33 males (84.6%). The median age of the patients was 34 years. The most frequent presenting complaint was fever, which was found in 37 patients (94.9%) followed by headache in 28 patients (71.8%), nausea and vomiting in 27 patients (69.2%), and seizures in 10 patients (25.6%). Overall, 39 patients underwent lumbar puncture, 27 patients (69.2%) had a positive motile trophozoites on CSF wet preparation microscopy, 18 patients (46.2%) had a positive culture, and 10 patients had a positive PCR. CSF analysis resembled bacterial meningitis with elevated white blood cell counts with predominantly neutrophils (median, 3000 [range, 1350-7500] cells/µL), low glucose levels median, 14 [range, 1-92] mg/dL), and elevated protein levels (median, 344 [range, 289-405] mg/dL). Imaging results were abnormal in approximately three-fourths of the patients which included cerebral edema (66.7%), hydrocephalus (25.6%), and cerebral infarctions (12.8%). Only one patient survived. PAM is a fatal illness with limited treatment success. Early diagnosis and prompt initiation of treatment can improve the survival of the patients and reduce mortality.
Assuntos
Amebíase , Infecções Protozoárias do Sistema Nervoso Central , Meningoencefalite , Naegleria fowleri , Masculino , Humanos , Adulto , Paquistão/epidemiologia , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/epidemiologia , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Punção Espinal , Amebíase/diagnóstico , Amebíase/epidemiologia , Meningoencefalite/diagnóstico , Meningoencefalite/epidemiologiaRESUMO
Naegleria fowleri is one of the free-living amoebae and is a causative agent of a lethal and rare central nervous system infection called primary amoebic meningoencephalitis. Despite the advancement in antimicrobial chemotherapy, the fatality rate in the reported cases is more than 95%. Most of the treatment drugs used against N. fowleri infection are repurposed drugs. Therefore, a large number of compounds have been tested against N. fowleri in vitro, but most of the compounds showed high toxicity. To overcome this, we evaluated the effectiveness of naturally occurring terpene compounds against N. fowleri. In this study, we evaluated the antiamoebic potential of natural compounds including Thymol, Borneol, Andrographolide, and Forskolin againstN. fowleri. Thymol showed the highest amoebicidal activity with IC50/24 h at 153.601 ± 19.6 µM. Two combinations of compounds Forskolin + Thymol and Forskolin + Borneol showed a higher effect on the viability of trophozoites as compared to compounds alone and hence showed a synergistic effect. The IC50 reported for Forskolin + Thymol was 81.30 ± 6.86 µM. Borneol showed maximum cysticidal activity with IC50/24 h at 192.605 ± 3.01 µM. Importantly, lactate dehydrogenase release testing revealed that all compounds displayed minimal cytotoxicity to human HaCaT, HeLa, and SH-SY5Y cell lines. The cytopathogenicity assay showed that Thymol and Borneol also significantly reduced the host cell cytotoxicity of pretreated amoeba toward the human HaCaT cell line. So, these terpene compounds hold potential as therapeutic agents against infections caused by N. fowleri and are potentially a step forward in drug development against this deadly pathogen as these compounds have also been reported to cross the blood-brain barrier. Therefore, an in vivo study using animal models is necessary to assess the efficacy of these compounds and the need for further research into the intranasal route of delivery for the treatment of these life-threatening infections.
Assuntos
Amoeba , Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Neuroblastoma , Animais , Humanos , Terpenos/farmacologia , Terpenos/uso terapêutico , Timol/farmacologia , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Colforsina/farmacologia , Células HeLaRESUMO
Primary amebic meningoencephalitis (PAM), a brain infection caused by a free-living ameba Naegleria fowleri, leads to an extensive inflammation of the brain and death within 1-18 (median 5) days after symptoms begin. Although natural products have played a significant role in the development of drugs for over a century, research focusing on identifying new natural product-based anti-N. fowleri agents is limited. We undertook a large-scale ATP bioluminescence-based screen of about 10,000 unique marine microbial metabolite mixtures against the trophozoites of N. fowleri. Our screen identified about 100 test materials with >90% inhibition at 50 µg/mL and a dose-response study found 20 of these active test materials exhibiting an EC50 ranging from 0.2 to 2 µg/mL. Examination of four of these potent metabolite mixtures, derived from our actinomycete strains CNT671, CNT756, and CNH301, resulted in the isolation of a pure metabolite identified as oligomycin D. Oligomycin D exhibited nanomolar potency on multiple genotypes of N. fowleri, and it was five- or 850-times more potent than the recommended drugs amphotericin B or miltefosine. Oligomycin D is fast-acting and reached its EC50 in 10 h, and it was also able to inhibit the invasiveness of N. fowleri significantly when tested on a matrigel invasion assay. Since oligomycin is known to manifest inhibitory activity against F1FO ATP synthase, we tested different F1FO ATP synthase inhibitors and identified a natural peptide leucinostatin as a fast-acting amebicidal compound with nanomolar potency on multiple strains.
Assuntos
Amebicidas , Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Humanos , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Rutamicina , Anfotericina B/farmacologiaRESUMO
Primary amebic meningoencephalitis (PAM) is a rare, but almost always fatal, central nervous system infection caused by Naegleria fowleri, which are thermophilic free-living amoeba. Here, we report the first case of PAM detected in South Korea, probably imported from Thailand. Despite antimicrobial treatment for N. fowleri infection with a combination of intravenous liposomal amphotericin B, fluconazole, azithromycin, and oral rifampin, the patient died 13 days after the onset of symptoms. Clinicians in South Korea treating severe meningoencephalitis, especially in individuals returning from tropical areas, are encouraged to include PAM in the differential diagnoses, given the accelerated global warming and increased overseas trips.
Assuntos
Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Humanos , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , República da Coreia , Administração Intravenosa , AzitromicinaRESUMO
Naegleria fowleri is a free-living thermophilic flagellate amoeba that causes a rare but life-threatening infection called primary amoebic meningoencephalitis (PAM), with a very high fatality rate. Herein, the anti-amoebic potential of carboxamide derivatives possessing sulfonyl or sulfamoyl moiety was assessed against pathogenic N. fowleri using amoebicidal, cytotoxicity and cytopathogenicity assays. The results from amoebicidal experiments showed that derivatives dramatically reduced N. fowleri viability. Selected derivatives demonstrated IC50 values at lower concentrations; 1j showed IC50 at 24.65 µM, while 1k inhibited 50% amoebae growth at 23.31 µM. Compounds with significant amoebicidal effects demonstrated limited cytotoxicity against human cerebral microvascular endothelial cells. Finally, some derivatives mitigated N. fowleri-instigated host cell death. Ultimately, this study demonstrated that 1j and 1k exhibited potent anti-amoebic activity and ought to be looked at in future studies for the development of therapeutic anti-amoebic pharmaceuticals. Further investigation is required to determine the clinical relevance of our findings.
Assuntos
Amebicidas , Amoeba , Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Humanos , Células Endoteliais , Amebicidas/farmacologia , Encéfalo/patologia , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológicoRESUMO
Naegleria fowleri is an opportunistic protozoan, belonging to the free-living amoeba group, that can be found in warm water bodies. It is causative agent the primary amoebic meningoencephalitis, a fulminant disease with a rapid progression that affects the central nervous system. However, no 100% effective treatments are available and those that are currently used involve the appearance of severe side effects, therefore, there is an urgent need to find novel antiamoebic compounds with low toxicity. In this study, the in vitro activity of six oxasqualenoids obtained from the red algae Laurencia viridis was evaluated against two different strains of N. fowleri (ATCC® 30808 and ATCC® 30215) as well as their cytotoxicity against murine macrophages. Yucatecone was the molecule with the highest selectivity index (>2.98 and 5.23 respectively) and it was selected to continue with the cell death type determination assays. Results showed that yucatone induced programmed cell death like responses in treated amoebae causing DNA condensation and cellular membrane damage among others. In this family of oxasqualenoids, it seems that the most significative structural feature to induce activity against N. fowleri is the presence of a ketone at C-18. This punctual oxidation transforms an inactive compound into a lead compound as the yucatecone and 18-ketodehydrotyrsiferol with IC50 values of 16.25 and 12.70 µM, respectively. The assessment of in silico ADME/Tox analysis revealed that the active compounds showed good Human Oral Absorption and demonstrate that are found to be within the limit of approved drug parameter range. Hence, the study highlights promising potential of yucatone to be tested for therapeutic use against primary amoebic meningoencephalitis.
Assuntos
Amoeba , Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Humanos , Animais , Camundongos , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológicoRESUMO
Naegleria fowleri is a pathogenic amoeba that causes a fulminant and rapidly progressive disease affecting the central nervous system called primary amoebic meningoencephalitis (PAM). Moreover, the disease is fatal in more than 97% of the reported cases, mostly affecting children and young people after practicing aquatic activities in nontreated fresh and warm water bodies contaminated with these amoebae. Currently, the treatment of primary amoebic meningoencephalitis is based on a combination of different antibiotics and antifungals, which are not entirely effective and lead to numerous side effects. In the recent years, research against PAM is focused on the search of novel, less toxic, and fully effective antiamoebic agents. Previous studies have reported the activity of cyano-substituted molecules in different protozoa. Therefore, the activity of 46 novel synthetic cyanomethyl vinyl ethers (QOET-51 to QOET-96) against two type strains of N. fowleri (ATCC 30808 and ATCC 30215) was determined. The data showed that QOET-51, QOET-59, QOET-64, QOET-67, QOET-72, QOET-77, and QOET-79 were the most active molecules. In fact, the selectivity index (CC50/IC50) was sixfold higher when compared to the activities of the drugs of reference. In addition, the mechanism of action of these compounds was studied, with the aim to demonstrate the induction of a programmed cell death process in N. fowleri.
Assuntos
Amoeba , Infecções Protozoárias do Sistema Nervoso Central , Naegleria fowleri , Criança , Humanos , Adolescente , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Éteres/farmacologiaRESUMO
A wide variety of diseases present with intracranial lesions. In this case report, a 67-year-old man initially presented to an outside hospital with nausea, headache, and ataxia and was found to have multiple intracranial lesions. Diagnostic workup was ultimately unrevealing, and his condition improved after a course of steroids and antibiotics. Unfortunately, symptoms returned 3 months later. MRI of the brain revealed progression of his intracranial lesions. This case highlights a diagnostic approach and general management strategy for patients presenting with undifferentiated intracranial pathology. A final diagnosis is ultimately reached and raises further discussion.
Assuntos
Antibacterianos , Encéfalo , Infecções Protozoárias do Sistema Nervoso Central , Hemianopsia , Humanos , Masculino , Idoso , Hemianopsia/etiologia , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Naegleria fowleri , Antibacterianos/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Free-living amebae (FLA) including Naegleria fowleri , Balamuthia mandrillaris , and Acanthamoeba species can cause rare, yet severe infections that are nearly always fatal. This review describes recent developments in epidemiology, diagnosis, and treatment of amebic meningoencephalitis. RECENT FINDINGS: Despite similarities among the three pathogenic FLA, there are notable variations in disease presentations, routes of transmission, populations at risk, and outcomes for each. Recently, molecular diagnostic tools have been used to diagnose a greater number of FLA infections. Treatment regimens for FLA have historically relied on survivor reports; more data is needed about novel treatments, including nitroxoline. SUMMARY: Research to identify new drugs and guide treatment regimens for amebic meningoencephalitis is lacking. However, improved diagnostic capabilities may lead to earlier diagnoses, allowing earlier treatment initiation and improved outcomes. Public health practitioners should continue to prioritize increasing awareness and providing education to clinicians, laboratorians, and the public about amebic infections.
Assuntos
Acanthamoeba , Amebíase , Infecções Protozoárias do Sistema Nervoso Central , Encefalite Infecciosa , Meningoencefalite , Humanos , Infecções Protozoárias do Sistema Nervoso Central/diagnóstico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/epidemiologia , Amebíase/diagnóstico , Amebíase/tratamento farmacológico , Amebíase/epidemiologia , Meningoencefalite/diagnóstico , Meningoencefalite/tratamento farmacológico , Meningoencefalite/epidemiologia , Encefalite Infecciosa/diagnóstico , Encefalite Infecciosa/tratamento farmacológico , Encefalite Infecciosa/epidemiologiaRESUMO
Primary amoebic meningoencephalitis is a rare but fatal central nervous system (CNS) disease caused by the "brain-eating amoeba" Naegleria fowleri. A major obstacle is the requirement for drugs with the ability to cross the blood-brain barrier, which are used in extremely high doses, cause severe side effects, and are usually ineffective. We discovered that the 4-aminomethylphenoxy-benzoxaborole AN3057 exhibits nanomolar potency against N. fowleri, and experimental treatment of infected mice significantly prolonged survival and demonstrated a 28% relapse-free cure rate.
Assuntos
Amebíase , Infecções Protozoárias do Sistema Nervoso Central , Meningoencefalite , Naegleria fowleri , Animais , Camundongos , Amebíase/tratamento farmacológico , Infecções Protozoárias do Sistema Nervoso Central/tratamento farmacológico , Barreira HematoencefálicaRESUMO
Naegleria fowleri, also known as the "brain-eating" amoeba, is a free-living protozoan that resides in freshwater bodies. This pathogenic amoeba infects humans as a casual event when swimming in contaminated water. Upon inhalation, N. fowleri invades the central nervous system and causes primary amoebic meningoencephalitis (PAM), a rapidly progressive and often fatal disease. Although PAM is considered rare, reducing its case fatality rate compels the search for pathogen-specific proteins with a structure-function relationship that favors their application as targets for discovering new or improved drugs against N. fowleri infections. Herein, we report a computational approach to study the structural features of Nf314 (a serine carboxypeptidase that is a virulence-related protein in N. fowleri infections) and assess its potential as a drug target, using bioinformatics tools and in silico molecular docking experiments. Our findings suggest that Nf314 has a ligand binding site suitable for the structure-based design of specific inhibitors. This study represents a further step toward postulating a reliable therapeutic target to treat PAM with drugs specifically aimed at blocking the pathogen proliferation by inhibiting protein function.