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Fulltext Systematic Review of Brain-Eating Amoeba: A Decade Update

Ahmad Zamzuri M'I, Abd Majid FN, Mihat M, Ibrahim SS, Ismail M, Abd Aziz S, et al.

Int J Environ Res Public Health, 2023 Feb 09;20(4).
PMID: 36833715 DOI: 10.3390/ijerph20043021

INTRODUCTION: Primary amoebic meningoencephalitis (PAM) is a rare but lethal infection of the brain caused by a eukaryote called Naegleria fowleri (N. fowleri). The aim of this review is to consolidate the recently published case reports of N. fowleri infection by describing its epidemiology and clinical features with the goal of ultimately disseminating this information to healthcare personnel.
METHODS: A comprehensive literature search was carried out using PubMed, Web of Science, Scopus, and OVID databases until 31 December 2022 by two independent reviewers. All studies from the year 2013 were extracted, and quality assessments were carried out meticulously prior to their inclusion in the final analysis.
RESULTS: A total of 21 studies were selected for qualitative analyses out of the 461 studies extracted. The cases were distributed globally, and 72.7% of the cases succumbed to mortality. The youngest case was an 11-day-old boy, while the eldest was a 75-year-old. Significant exposure to freshwater either from recreational activities or from a habit of irrigating the nostrils preceded onset. The symptoms at early presentation included fever, headache, and vomiting, while late sequalae showed neurological manifestation. An accurate diagnosis remains a challenge, as the symptoms mimic bacterial meningitis. Confirmatory tests include the direct visualisation of the amoeba or the use of the polymerase chain reaction method.
CONCLUSIONS: N. fowleri infection is rare but leads to PAM. Its occurrence is worldwide with a significant risk of fatality. The suggested probable case definition based on the findings is the acute onset of fever, headache, and vomiting with meningeal symptoms following exposure to freshwater within the previous 14 days. Continuous health promotion and health education activities for the public can help to improve knowledge and awareness prior to engagement in freshwater activities.

Matched MeSH terms: Naegleria fowleri*
Biology and pathogenesis of Naegleria fowleri

Siddiqui R, Ali IK, Cope JR, Khan NA

Acta Trop, 2016 Dec;164:375-394.
PMID: 27616699 DOI: 10.1016/j.actatropica.2016.09.009

Naegleria fowleri is a protist pathogen that can cause lethal brain infection. Despite decades of research, the mortality rate related with primary amoebic meningoencephalitis owing to N. fowleri remains more than 90%. The amoebae pass through the nose to enter the central nervous system killing the host within days, making it one of the deadliest opportunistic parasites. Accordingly, we present an up to date review of the biology and pathogenesis of N. fowleri and discuss needs for future research against this fatal infection.

Matched MeSH terms: Naegleria fowleri*
Anti-amoebic effects of synthetic acridine-9(10H)-one against brain-eating amoebae

Ahmed U, Manzoor M, Qureshi S, Mazhar M, Fatima A, Aurangzeb S, et al.

Acta Trop, 2023 Mar;239:106824.
PMID: 36610529 DOI: 10.1016/j.actatropica.2023.106824

Pathogenic A. castellanii and N. fowleri are opportunistic free-living amoebae. Acanthamoeba spp. are the causative agents of granulomatous amebic encephalitis (GAE) and amebic keratitis (AK), whereas Naegleria fowleri causes a very rare but severe brain infection called primary amebic meningoencephalitis (PAM). Acridinone is an important heterocyclic scaffold and both synthetic and naturally occurring derivatives have shown various valuable biological properties. In the present study, ten synthetic Acridinone derivatives (I-X) were synthesized and assessed against both amoebae for anti-amoebic and cysticidal activities in vitro. In addition, excystation, encystation, cytotoxicity, host cell pathogenicity was also performed in-vitro. Furthermore, molecular docking studies of these compounds with three cathepsin B paralogous enzymes of N. fowleri were performed in order to predict the possible docking mode with pathogen. Compound VII showed potent anti-amoebic activity against A. castellanii with IC50 53.46 µg/mL, while compound IX showed strong activity against N. fowleri in vitro with IC50 72.41 µg/mL. Compounds II and VII showed a significant inhibition of phenotypic alteration of A. castellanii, while compound VIII significantly inhibited N. fowleri cysts. Cytotoxicity assessment showed that these compounds caused minimum damage to human keratinocyte cells (HaCaT cells) at 100 µg/mL, while also effectively reduced the cytopathogenicity of Acanthamoeba to HaCaT cells. Moreover, Cathepsin B protease was investigated in-silico as a new molecular therapeutic target for these compounds. All compounds showed potential interactions with the catalytic residues. These results showed that acridine-9(10H)-one derivatives, in particular compounds II, VII, VIII and IX hold promise in the development of therapeutic agents against these free-living amoebae.

Matched MeSH terms: Naegleria fowleri*
Natural Terpenes Inhibit the Cytopathogenicity of Naegleria fowleri Causing Primary Amoebic Meningoencephalitis in the Human Cell Line Model

Rajendran K, Ahmed U, Meunier AC, Shaikh MF, Siddiqui R, Anwar A

ACS Chem Neurosci, 2023 Dec 06;14(23):4105-4114.
PMID: 37983556 DOI: 10.1021/acschemneuro.3c00258

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.

Matched MeSH terms: Naegleria fowleri*
Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

Mungroo MR, Anwar A, Khan NA, Siddiqui R

Mini Rev Med Chem, 2019;19(12):980-987.
PMID: 30868950 DOI: 10.2174/1389557519666190313161854

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.

Matched MeSH terms: Naegleria fowleri/drug effects*; Naegleria fowleri/parasitology*
Synthetic nanoparticle-conjugated bisindoles and hydrazinyl arylthiazole as novel antiamoebic agents against brain-eating amoebae

Kanwal, Mungroo MR, Anwar A, Ali F, Khan S, Abdullah MA, et al.

Exp Parasitol, 2020 Nov;218:107979.
PMID: 32866583 DOI: 10.1016/j.exppara.2020.107979

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.

Matched MeSH terms: Naegleria fowleri
Brain-Eating Amoebae: Silver Nanoparticle Conjugation Enhanced Efficacy of Anti-Amoebic Drugs against Naegleria fowleri

Rajendran K, Anwar A, Khan NA, Siddiqui R

ACS Chem Neurosci, 2017 12 20;8(12):2626-2630.
PMID: 29206032 DOI: 10.1021/acschemneuro.7b00430

The overall aim of this study was to determine whether conjugation with silver nanoparticles enhances effects of available drugs against primary amoebic meningoencephalitis due to Naegleria fowleri. Amphotericin B, Nystatin, and Fluconazole were conjugated with silver nanoparticles, and synthesis was confirmed using UV-visible spectrophotometry. Atomic force microscopy determined their size in range of 20-100 nm. To determine amoebicidal effects, N. fowleri were incubated with drugs-conjugated silver nanoparticles, silver nanoparticles alone, and drugs alone. The findings revealed that silver nanoparticles conjugation significantly enhanced antiamoebic effects of Nystatin and Amphotericin B but not Fluconazole at micromolar concentrations, compared with the drugs alone. For the first time, our findings showed that silver nanoparticle conjugation enhances efficacy of antiamoebic drugs against N. fowleri. Given the rarity of the disease and challenges in developing new drugs, it is hoped that modifying existing drugs to enhance their antiamoebic effects is a useful avenue that holds promise in improving the treatment of brain-eating amoebae infection due to N. fowleri.

Matched MeSH terms: Naegleria fowleri/cytology; Naegleria fowleri/drug effects*; Naegleria fowleri/physiology*
trans-Cinnamic Acid Conjugated Gold Nanoparticles as Potent Therapeutics against Brain-Eating Amoeba Naegleria fowleri

Rajendran K, Anwar A, Khan NA, Shah MR, Siddiqui R

ACS Chem Neurosci, 2019 06 19;10(6):2692-2696.
PMID: 30970208 DOI: 10.1021/acschemneuro.9b00111

Primary amoebic meningoencephalitis (PAM), a deadly brain infection, is caused by brain-eating amoeba Naegleria fowleri. The current first line of treatment against PAM is a mixture of amphotericin B, rifampin, and miltefosine. Since, no single effective drug has been developed so far, the mortality rate is above 95%. Moreover, severe adverse side effects are associated with these drugs. Nanotechnology has provided several advances in biomedical applications especially in drug delivery and diagnosis. Herein, for the first time we report antiamoebic properties of cinnamic acid (CA) and gold nanoparticles conjugated with CA (CA-AuNPs) against N. fowleri. CA-AuNPs were successfully synthesized by sodium borohydride reduction of tetrachloroauric acid. Size and morphology were determined by atomic force microscopy (AFM) while the surface plasmon resonance band was analyzed by ultraviolet-visible (UV-vis) spectrophotometry for the characterization of the nanoparticles. Amoebicidal and cytopathogenicity (host cell cytotoxicity) assays revealed that both CA and CA-AuNPs displayed significant anti- N. fowleri properties ( P < 0.05), whereas nanoparticles conjugation further enhanced the anti- N. fowleri effects of CA. This study established a potential drug lead, while CA-AuNPs appear to be promising candidate for drug discovery against PAM.

Matched MeSH terms: Naegleria fowleri/drug effects*
Fulltext Brain-Eating Amoebae: Predilection Sites in the Brain and Disease Outcome

Ong TYY, Khan NA, Siddiqui R

J Clin Microbiol, 2017 07;55(7):1989-1997.
PMID: 28404683 DOI: 10.1128/JCM.02300-16

Acanthamoeba spp. and Balamuthia mandrillaris are causative agents of granulomatous amoebic encephalitis (GAE), while Naegleria fowleri causes primary amoebic meningoencephalitis (PAM). PAM is an acute infection that lasts a few days, while GAE is a chronic to subacute infection that can last up to several months. Here, we present a literature review of 86 case reports from 1968 to 2016, in order to explore the affinity of these amoebae for particular sites of the brain, diagnostic modalities, treatment options, and disease outcomes in a comparative manner.

Matched MeSH terms: Naegleria fowleri/isolation & purification*
Development of nanoparticle-assisted PCR assay in the rapid detection of brain-eating amoebae

Gabriel S, Rasheed AK, Siddiqui R, Appaturi JN, Fen LB, Khan NA

Parasitol Res, 2018 Jun;117(6):1801-1811.
PMID: 29675682 DOI: 10.1007/s00436-018-5864-0

Brain-eating amoebae (Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri) have gained increasing attention owing to their capacity to produce severe human and animal infections involving the brain. Early detection is a pre-requisite in successful prognosis. Here, we developed a nanoPCR assay for the rapid detection of brain-eating amoebae using various nanoparticles. Graphene oxide, copper and alumina nanoparticles used in this study were characterized using Raman spectroscopy measurements through excitation with a He-Ne laser, while powder X-ray diffraction patterns were taken on a PANanalytical, X'Pert HighScore diffractometer and the morphology of the materials was confirmed using high-resolution transmission electron microscopy (HRTEM). Using nanoparticle-assisted PCR, the results revealed that graphene oxide, copper oxide and alumina nanoparticles significantly enhanced PCR efficiency in the detection of pathogenic free-living amoebae using genus-specific probes. The optimal concentration of graphene oxide, copper oxide and alumina nanoparticles for Acanthamoeba spp. was determined at 0.4, 0.04 and 0.4 μg per mL respectively. For B. mandrillaris, the optimal concentration was determined at 0.4 μg per mL for graphene oxide, copper oxide and alumina nanoparticles, and for Naegleria, the optimal concentration was 0.04, 4.0 and 0.04 μg per mL respectively. Moreover, combinations of these nanoparticles proved to further enhance PCR efficiency. The addition of metal oxide nanoparticles leads to excellent surface effect, while thermal conductivity property of the nanoparticles enhances PCR productivity. These findings suggest that nanoPCR assay has tremendous potential in the clinical diagnosis of parasitic infections as well as for studying epidemiology and pathology and environmental monitoring of other microbes.

Matched MeSH terms: Naegleria fowleri/genetics*; Naegleria fowleri/isolation & purification
Future Priorities in Tackling Infections Due to Brain-Eating Amoebae

Khan NA, Anwar A, Siddiqui R

ACS Chem Neurosci, 2017 11 15;8(11):2355.
PMID: 28933530 DOI: 10.1021/acschemneuro.7b00343

Brain-eating amoebae (Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri) can cause opportunistic infections involving the central nervous system. It is troubling that the mortality rate is more than 90% despite advances in antimicrobial chemotherapy over the last few decades. Here, we describe urgent key priorities for improving outcomes from infections due to brain-eating amoebae.

Matched MeSH terms: Naegleria fowleri/drug effects; Naegleria fowleri/genetics
Repositioning of Guanabenz in Conjugation with Gold and Silver Nanoparticles against Pathogenic Amoebae Acanthamoeba castellanii and Naegleria fowleri

Anwar A, Mungroo MR, Anwar A, Sullivan WJ, Khan NA, Siddiqui R

ACS Infect Dis, 2019 Dec 13;5(12):2039-2046.
PMID: 31612700 DOI: 10.1021/acsinfecdis.9b00263

Brain-eating amoebae cause devastating infections in the central nervous system of humans, resulting in a mortality rate of 95%. There are limited effective therapeutic options available clinically for treating granulomatous amoebic encephalitis and primary amoebic meningoencephalitis caused by Acanthamoeba castellanii (A. castellanii) and Naegleria fowleri (N. fowleri), respectively. Here, we report for the first time that guanabenz conjugated to gold and silver nanoparticles has significant antiamoebic activity against both A. castellanii and N. fowleri. Gold and silver conjugated guanabenz nanoparticles were synthesized by the one-phase reduction method and were characterized by ultraviolet-visible spectrophotometry and atomic force microscopy. Both metals were facilely stabilized by the coating of guanabenz, which was examined by surface plasmon resonance determination. The average size of gold nanoconjugated guanabenz was found to be 60 nm, whereas silver nanoparticles were produced in a larger size distribution with the average diameter of around 100 nm. Guanabenz and its noble metal nanoconjugates exhibited potent antiamoebic effects in the range of 2.5 to 100 μM against both amoebae. Nanoparticle conjugation enhanced the antiamoebic effects of guanabenz, as more potent activity was observed at a lower effective concentration (2.5 and 5 μM) compared to the drug alone. Moreover, encystation and excystation assays revealed that guanabenz inhibits the interconversion between the trophozoite and cyst forms of A. castellanii. Cysticdal effects against N. fowleri were also observed. Notably, pretreatment of A. castellanii with guanabenz and its nanoconjugates exhibited a significant reduction in the host cell cytopathogenicity from 65% to 38% and 2% in case of gold and silver nanoconjugates, respectively. Moreover, the cytotoxic evaluation of guanabenz and its nanoconjugates revealed negligible cytotoxicity against human cells. Guanabenz is already approved for hypertension and crosses the blood-brain barrier; the results of our current study suggest that guanabenz and its conjugated gold and silver nanoparticles can be repurposed as a potential drug for treating brain-eating amoebic infections.

Matched MeSH terms: Naegleria fowleri/drug effects*; Naegleria fowleri/growth & development
Fulltext Novel Azoles as Antiparasitic Remedies against Brain-Eating Amoebae

Anwar A, Mungroo MR, Khan S, Fatima I, Rafique R, Kanwal, et al.

Antibiotics (Basel), 2020 Apr 17;9(4).
PMID: 32316387 DOI: 10.3390/antibiotics9040188

Balamuthia mandrillaris and Naegleriafowleri are opportunistic protozoan pathogens capable of producing infection of the central nervous system with more than 95% mortality rate. Previously, we have synthesized several compounds with antiamoebic properties; however, synthesis of compounds that are analogues of clinically used drugs is a highly desirable approach that can lead to effective drug development against these devastating infections. In this regard, compounds belonging to the azole class possess wide range of antimicrobial properties and used clinically. In this study, six novel benzimidazole, indazole, and tetrazole derivatives were synthesized and tested against brain-eating amoebae. These compounds were tested for their amoebicidal and static properties against N. fowleri and B. mandrillaris. Furthermore, the compounds were conjugated with silver nanoparticles and characterized. The synthetic heterocyclic compounds showed up to 72% and 65% amoebicidal activities against N. fowleri and B. mandrillaris respectively, while expressing up to 75% and 70% amoebistatic activities, respectively. Following conjugation with silver nanoparticles, amoebicidal activities of the drugs increased by up to 46 and 36% versus B. mandrillaris and N. fowleri. Minimal effects were observed when the compounds were evaluated against human cells using cytotoxicity assays. In summary, azole compounds exhibited potent activity against N. fowleri and B. mandrillaris. Moreover, conjugation of the azole compounds with silver nanoparticles further augmented the capabilities of the compounds against amoebae.

Matched MeSH terms: Naegleria fowleri
Fulltext Gold-Conjugated Curcumin as a Novel Therapeutic Agent against Brain-Eating Amoebae

Mungroo MR, Anwar A, Khan NA, Siddiqui R

ACS Omega, 2020 Jun 02;5(21):12467-12475.
PMID: 32548431 DOI: 10.1021/acsomega.0c01305

Balamuthia mandrillaris and Naegleria fowleri are free-living amoebae that cause infection of the central nervous system, granulomatous amoebic encephalitis (GAE) and primary amoebic meningoencephalitis (PAM), respectively. The fact that mortality rates for cases of GAE and PAM are more than 95% indicates the need for new therapeutic agents against those amoebae. Considering that curcumin exhibits a wide range of biological properties and has shown efficacy against Acanthamoeba castellanii, we evaluated the amoebicidal properties of curcumin against N. fowleri and B. mandrillaris. Curcumin showed significant amoebicidal activities with an AC50 of 172 and 74 μM against B. mandrillaris and N. fowleri, respectively. Moreover, these compounds were also conjugated with gold nanoparticles to further increase their amoebicidal activities. After conjugation with gold nanoparticles, amoebicidal activities of the drugs were increased by up to 56 and 37% against B. mandrillaris and N. fowleri, respectively. These findings are remarkable and suggest that clinically available curcumin and our gold-conjugated curcumin nanoparticles hold promise in the improved treatment of fatal infections caused by brain-eating amoebae and should serve as a model in the rationale development of therapeutic interventions against other infections.

Matched MeSH terms: Naegleria fowleri
Clinically Approved Drugs against CNS Diseases as Potential Therapeutic Agents To Target Brain-Eating Amoebae

Anwar A, Rajendran K, Siddiqui R, Raza Shah M, Khan NA

ACS Chem Neurosci, 2019 01 16;10(1):658-666.
PMID: 30346711 DOI: 10.1021/acschemneuro.8b00484

Central nervous system (CNS) infections caused by free-living amoebae such as Acanthamoeba species and Naegleria fowleri are rare but fatal. A major challenge in the treatment against the infections caused by these amoebae is the discovery of novel compounds that can effectively cross the blood-brain barrier to penetrate the CNS. It is logical to test clinically approved drugs against CNS diseases for their potential antiamoebic effects since they are known for effective blood-brain barrier penetration and affect eukaryotic cell targets. The antiamoebic effects of clinically available drugs for seizures targeting gamma-amino butyric acid (GABA) receptor and ion channels were tested against Acanthamoeba castellanii belonging to the T4 genotype and N. fowleri. Three such drugs, namely, diazepam (Valium), phenobarbitone (Luminal), phenytoin (Dilantin), and their silver nanoparticles (AgNPs) were evaluated against both trophozoites and cysts stage. Drugs alone and drug conjugated silver nanoparticles were tested for amoebicidal, cysticidal, and host-cell cytotoxicity assays. Nanoparticles were synthesized by sodium borohydride reduction of silver nitrate with drugs as capping agents. Drug conjugated nanoconjugates were characterized by ultraviolet-visible (UV-vis) and Fourier transform infrared (FT-IR) spectroscopies and atomic force microscopy (AFM). In vitro moebicidal assay showed potent amoebicidal effects for diazepam, phenobarbitone, and phenytoin-conjugated AgNPs as compared to drugs alone against A. castellanii and N. fowleri. Furthermore, both drugs and drug conjugated AgNPs showed compelling cysticidal effects. Drugs conjugations with silver nanoparticles enhanced their antiacanthamoebic activity. Interestingly, amoeba-mediated host-cell cytotoxicity was also significantly reduced by drugs alone as well as their nanoconjugates. Since, these drugs are being used to target CNS diseases, their evaluation against brain-eating amoebae seems feasible due to advantages such as permeability of the blood-brain barrier, established pharmacokinetics and dynamics, and United States Food and Drug Administration (FDA) approval. Given the limited availability of effective drugs against brain-eating amoebae, the clinically available drugs tested here present potential for further in vivo studies.

Matched MeSH terms: Naegleria fowleri/drug effects*
Naegleria fowleri: differential genetic expression following treatment with Hesperidin conjugated with silver nanoparticles using RNA-Seq

Siddiqui R, Rajendran K, Abdella B, Ayub Q, Lim SY, Khan NA

Parasitol Res, 2020 Jul;119(7):2351-2358.
PMID: 32451717 DOI: 10.1007/s00436-020-06711-6

Naegleria fowleri causes a deadly infection known as primary amoebic meningoencephalitis (PAM). To our knowledge, there are very few transcriptome studies conducted on these brain-eating amoebae, despite rise in the number of cases. Although the Naegleria genome has been sequenced, currently, it is not well annotated. Transcriptome level studies are needed to help understand the pathology and biology of this fatal parasitic infection. Recently, we showed that nanoparticles loaded with the flavonoid Hesperidin (HDN) are potential novel antimicrobial agents. N. fowleri trophozoites were treated with and without HDN-conjugated with silver nanoparticles (AgNPs) and silver only, and then, 50% minimum inhibitory concentration (MIC) was determined. The results revealed that the MIC of HDN-conjugated AgNPs was 12.5 microg/mL when treated for 3 h. As no reference genome exists for N. fowleri, de novo RNA transcriptome analysis using RNA-Seq and differential gene expression analysis was performed using the Trinity software. Analysis revealed that more than 2000 genes were differentially expressed in response to N. fowleri treatment with HDN-conjugated AgNPs. Some of the genes were linked to oxidative stress response, DNA repair, cell division, cell signalling and protein synthesis. The downregulated genes were linked with processes such as protein modification, synthesis of aromatic amino acids, when compared with untreated N. fowleri. Further transcriptome studies will lead to understanding of genetic mechanisms of the biology and pathogenesis and/or the identification of much needed drug candidates.

Matched MeSH terms: Naegleria fowleri/genetics*
Oleic Acid Coated Silver Nanoparticles Showed Better in Vitro Amoebicidal Effects against Naegleria fowleri than Amphotericin B

Rajendran K, Anwar A, Khan NA, Aslam Z, Raza Shah M, Siddiqui R

ACS Chem Neurosci, 2020 08 19;11(16):2431-2437.
PMID: 31347828 DOI: 10.1021/acschemneuro.9b00289

Naegleria fowleri (N. fowleri) causes primary amoebic meningoencephalitis (PAM) which almost always results in death. N. fowleri is also known as "brain-eating amoeba" due to its literal infestation of the brain leading to an inflammatory response in the brain tissues. Currently, there is no single drug that is available to treat PAM, and most treatments are combinations of antifungal, anticancer, and anti-inflammatory drugs. Recently nanotechnology has gained attention in chemotherapeutic research converging on drug delivery, while oleic acid (OA) has shown positive effects on the human immune system and inflammatory processes. In continuation of our recent research in which we reported the effects of oleic acid conjugated with silver nanoparticles (OA-AgNPs) against free-living amoeba Acanthamoeba castellanii, in this report, we show their antiamoebic effects against N. fowleri. OA alone and its nanoconjugates were tested against the amoeba by using amoebicidal and host cell cytopathogenicity assays. Trypan blue exclusion assay was used to determine cell viability. The results revealed that OA-AgNPs exhibited significantly enhanced antiamoebic effects (P < 0.05) against N. fowleri as compared to OA alone. Evidently, lactate dehydrogenase release shows reduced N. fowleri-mediated host cell cytotoxicity. Based on our study, we anticipate that further studies on OA-AgNPs could potentially provide an alternative treatment of PAM.

Matched MeSH terms: Naegleria fowleri
Fulltext Proteinases in Naegleria Fowleri (strain NF3), a pathogenic amoeba: a preliminary study

Mat Amin N

Trop Biomed, 2004 Dec;21(2):57-60.
PMID: 16493399

Naegleria fowleri is a free-living amoeba, known as a causative agent for a fatal disease of the central nervous system (CNS) in man such as Primary amoebic meningoencephalitis (PAM). Factors contributing to its pathogenicity and its distribution in the environment have been investigated by previous researchers. In case of its pathogenicity, several enzymes such as phospolipase A and sphingomyelinase, have been proposed to probably act as aggressors in promoting PAM but no study so far have been conducted to investigate the presence of proteinase enzyme in this amoeba although a 56kDa cystein proteinase enzyme has been identified in Entamoeba histolytica as an important contributing factor in the amoeba's virulence. In this preliminary study, a pathogenic amoeba, Naegleria fowleri (strain NF3) was examined for the presence of proteinases. Samples of enzymes in this amoeba were analysed by electrophoresis using SDS-PAGE-gelatin gels. The results showed that this amoeba possesses at least two high molecular weight proteinases on gelatin gels; their apparent molecular weights are approximately 128 kDa and approximately 170 kDa. Band of approximately 128 kDa enzyme is membrane-associated and its activity is higher at alkaline pH compared with lower pH; at lower pH, its activity is greatly stimulated by DTT. The approximately 170 kDa band enzyme appears to be inactivated at pH 8.0, at lower ph its activity is higher and DTT-dependance. The activity of this enzyme is partially inhibited by inhibitor E-64 but markedly inhibited to antipain suggesting it belongs to the cysteine proteinase group.

Matched MeSH terms: Naegleria fowleri
Aryl Quinazolinone Derivatives as Novel Therapeutic Agents against Brain-Eating Amoebae

Mungroo MR, Shahbaz MS, Anwar A, Saad SM, Khan KM, Khan NA, et al.

ACS Chem Neurosci, 2020 08 19;11(16):2438-2449.
PMID: 31961126 DOI: 10.1021/acschemneuro.9b00596

Naegleria fowleri and Balamuthia mandrillaris are protist pathogens that infect the central nervous system, causing primary amoebic meningoencephalitis and granulomatous amoebic encephalitis with mortality rates of over 95%. Quinazolinones and their derivatives possess a wide spectrum of biological properties, but their antiamoebic effects against brain-eating amoebae have never been tested before. In this study, we synthesized a variety of 34 novel arylquinazolinones derivatives (Q1-Q34) by altering both quinazolinone core and aryl substituents. To study the antiamoebic activity of these synthetic arylquinazolinones, amoebicidal and amoebistatic assays were performed against N. fowleri and B. mandrillaris. Moreover, amoebae-mediated host cells cytotopathogenicity and cytotoxicity assays were performed against human keratinocytes cells in vitro. The results revealed that selected arylquinazolinones derivatives decreased the viability of B. mandrillaris and N. fowleri significantly (P < 0.05) and reduced cytopathogenicity of both parasites. Furthermore, these compounds were also found to be least cytotoxic against HaCat cells. Considering that nanoparticle-based materials possess potent in vitro activity against brain-eating amoebae, we conjugated quinazolinones derivatives with silver nanoparticles and showed that activities of the drugs were enhanced successfully after conjugation. The current study suggests that quinazolinones alone as well as conjugated with silver nanoparticles may serve as potent therapeutics against brain-eating amoebae.

Matched MeSH terms: Naegleria fowleri
Repurposing of Drugs Is a Viable Approach to Develop Therapeutic Strategies against Central Nervous System Related Pathogenic Amoebae

Anwar A, Khan NA, Siddiqui R

ACS Chem Neurosci, 2020 08 19;11(16):2378-2384.
PMID: 32073257 DOI: 10.1021/acschemneuro.9b00613

Brain-eating amoebae including Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris cause rare infections of the central nervous system that almost always result in death. The high mortality rate, lack of interest for drug development from pharmaceutical industries, and no available effective drugs present an alarming challenge. The current drugs employed in the management and therapy of these devastating diseases are amphotericin B, miltefosine, chlorhexidine, pentamidine, and voriconazole which are generally used in combination. However, clinical evidence shows that these drugs have limited efficacy and high host cell cytotoxicity. Repurposing of drugs is a practical approach to utilize commercially available, U.S. Food and Drug Administration approved drugs for one disease against rare diseases caused by brain-eating amoebae. In this Perspective, we highlight some of the success stories of drugs repositioned against neglected parasitic diseases and identify future potential for effective and sustainable drug development against brain-eating amoebae infections.

Matched MeSH terms: Naegleria fowleri

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