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Antibiotics (Basel, Switzerland) May 2022Naegleria fowleri and Balamuthia mandrillaris are pathogenic free-living amoebae that infect the central nervous system with over 95% mortality rates. Although several...
Naegleria fowleri and Balamuthia mandrillaris are pathogenic free-living amoebae that infect the central nervous system with over 95% mortality rates. Although several compounds have shown promise in vitro but associated side effects and/or prolonged approval processes for clinical applications have led to limited success. To overcome this, drug repurposing of marketed compounds with known mechanism of action is considered a viable approach that has potential to expedite discovery and application of anti-amoebic compounds. In fact, many of the drugs currently employed in the treatment of N. fowleri and B. mandrillaris, such as amphotericin B, fluconazole, rifampin and miltefosine, are repurposed drugs. Here, we evaluated a range of clinical and laboratory compounds including metformin, quinclorac, indaziflam, inositol, nateglinide, 2,6-DNBT, trans-cinnamic acid, terbuthylazine, acarbose, glimepiride, vildagliptin, cellulase, thaxtomin A, repaglinide and dimethyl peptidase (IV) inhibitor against N. fowleri and B. mandrillaris. Anti-amoebic assays revealed that indaziflam, nateglinide, 2,6-DNBT, terbuthylazine, acarbose and glimepiride exhibited potent amoebicidal properties against both N. fowleri and B. mandrillaris. Notably, all compounds tested showed minimal human (HaCaT) cell cytotoxicity as determined by lactate dehydrogenase release. Prospective research using animal models is warranted to determine the potential of these repurposed compounds, as well as the need for investigating the intranasal route of delivery to treat these devastating infections.
PubMed: 35740156
DOI: 10.3390/antibiotics11060749 -
Antibiotics (Basel, Switzerland) Sep 2022and are opportunistic protists, responsible for fatal central nervous system infections such as primary amoebic meningoencephalitis (PAM) and granulomatous amoebic...
and are opportunistic protists, responsible for fatal central nervous system infections such as primary amoebic meningoencephalitis (PAM) and granulomatous amoebic encephalitis (GAE) with mortality rates higher than 90%. Threatening a rise in cases is the increase in temperature due to global warming. No effective treatment is currently available. Herein, nanotechnology was used to conjugate Zinc oxide with Ampicillin, Ceftrixon, Naringin, Amphotericin B, and Quericitin, and the amoebicidal activity and host cell cytotoxicity of these resulting compounds were investigated. The compounds ZnO-CD-AMPi, ZnO-CD-CFT, ZnO-CD-Nar, ZnO-CD-AMB, and ZnO-CD-QT were found to reduce viability to 35.5%, 39.6%, 52.0%, 50.8%, 35.9%, and 69.9%, respectively, and viability to 40.9%, 48.2%, 51.6%, 43.8%, and 62.4%, respectively, when compared with their corresponding controls. Furthermore, the compounds reduced -mediated and -mediated host cell death significantly. Additionally, the compounds showed limited cytotoxicity against human cells; cell toxicity was 35.5%, 36.4%, 30.9%, 36.6%, and 35.6%, respectively, for the compounds ZnO-CD-AMPi, ZnO-CD-CFT, ZnO-CD-Nar, ZnO-CD-AMB, and ZnO-CD-QT. Furthermore, the minimum inhibitory concentrations to inhibit amoeba growth by 50% were determined for and The MIC for were determined to be 69.52 µg/mL, 82.05 µg/mL, 88.16 µg/mL, 95.61 µg/mL, and 85.69 µg/mL, respectively; the MIC of the compounds for were determined to be 113.9 µg/mL, 102.3 µg/mL, 106.9 µg/mL, 146.4 µg/mL, and 129.6 µg/mL, respectively. Translational research to further develop therapies based on these compounds is urgently warranted, given the lack of effective therapies currently available against these devastating infections.
PubMed: 36289939
DOI: 10.3390/antibiotics11101281 -
The Journal of International Medical... May 2022is a free-living heterotrophic amoeba found in soil that causes a rare and usually fatal granulomatous amebic encephalitis. We report an immunocompetent patient...
is a free-living heterotrophic amoeba found in soil that causes a rare and usually fatal granulomatous amebic encephalitis. We report an immunocompetent patient infected with encephalitis diagnosed by next-generation sequencing (NGS). Clinical manifestations included sudden headache and epilepsy with disturbance of consciousness. The opening pressure of cerebrospinal fluid (CSF) was 220 mmHO, with mildly elevated white blood cell numbers and elevated protein levels. Cranial magnetic resonance imaging revealed abnormal signals in the right frontal lobe, left parietal lobe, and left occipital lobe. CSF NGS detected . Albendazole and metronidazole combined with fluconazole were administered to the patient immediately, but his condition deteriorated and he eventually died. Encephalitis caused by is rare and has a high mortality rate. Clinical manifestations are complex and diverse, but early diagnosis is very important for successful treatment. This can be aided by the metagenomic NGS of CSF.
Topics: Amebiasis; Balamuthia mandrillaris; Encephalitis; High-Throughput Nucleotide Sequencing; Humans; Magnetic Resonance Imaging; Male
PubMed: 35505464
DOI: 10.1177/03000605221093217 -
JMM Case Reports Jun 2016This case report describes a human survivor of infection. This is a free-living amoeba that can cause infection with the devastating consequence of near universally...
INTRODUCTION
This case report describes a human survivor of infection. This is a free-living amoeba that can cause infection with the devastating consequence of near universally fatal encephalitis. We report this case to demonstrate the possibility of recovery.
CASE PRESENTATION
A 26-year-old Hispanic male, a landscape gardener, presented to the hospital in March 2010 with a two month history of headache, visual disturbances and new-onset seizures. Brain imaging identified two enhancing central lesions and was later identified by brain biopsy. He received several months of various antimicrobials including miltefosine, a novel use of the drug in this disease at the time. Seven weeks into therapy, considerations were made to switch him to 'comfort care' because of worsening clinical status and seemingly lack of response to treatment. The patient finally demonstrated clinical and radiological improvement after eight weeks with modified therapy, despite experiencing some debilitating toxic effects likely to be related to antibiotics. Two years after his initial presentation he made a complete recovery.
CONCLUSION
amoebic encephalitis is considered an almost universally fatal disease; this case demonstrates the possibility of recovery. This report outlines his treatment, drug toxicities and includes additional information regarding the therapeutic use of the drug miltefosine. Whether his survival is related to the specific antimicrobials used in this case is unknown and further investigation is warranted.
PubMed: 28348755
DOI: 10.1099/jmmcr.0.005031 -
Scientific Reports Nov 2021Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a 'brain-eating' disease. As with...
Balamuthia mandrillaris, a pathogenic free-living amoeba, causes cutaneous skin lesions as well as granulomatous amoebic encephalitis, a 'brain-eating' disease. As with the other known pathogenic free-living amoebas (Naegleria fowleri and Acanthamoeba species), drug discovery efforts to combat Balamuthia infections of the central nervous system are sparse; few targets have been validated or characterized at the molecular level, and little is known about the biochemical pathways necessary for parasite survival. Current treatments of encephalitis due to B. mandrillaris lack efficacy, leading to case fatality rates above 90%. Using our recently published methodology to discover potential drugs against pathogenic amoebas, we screened a collection of 85 compounds with known antiparasitic activity and identified 59 compounds that impacted the growth of Balamuthia trophozoites at concentrations below 220 µM. Since there is no fully annotated genome or proteome of B. mandrillaris, we sequenced and assembled its transcriptome from a high-throughput RNA-sequencing (RNA-Seq) experiment and located the coding sequences of the genes potentially targeted by the growth inhibitors from our compound screens. We determined the sequence of 17 of these target genes and obtained expression clones for 15 that we validated by direct sequencing. These will be used in the future in combination with the identified hits in structure guided drug discovery campaigns to develop new approaches for the treatment of Balamuthia infections.
Topics: Acanthamoeba; Amebiasis; Amoeba; Balamuthia mandrillaris; Base Sequence; Brain; Drug Design; Drug Discovery; Encephalitis; Gene Expression; Naegleria fowleri; Transcriptome; Trophozoites
PubMed: 34737367
DOI: 10.1038/s41598-021-99903-8 -
Clinical Microbiology Reviews Jul 2008Balamuthia mandrillaris is an emerging protozoan parasite, an agent of granulomatous amoebic encephalitis involving the central nervous system, with a case fatality rate... (Review)
Review
Balamuthia mandrillaris is an emerging protozoan parasite, an agent of granulomatous amoebic encephalitis involving the central nervous system, with a case fatality rate of >98%. This review presents our current understanding of Balamuthia infections, their pathogenesis and pathophysiology, and molecular mechanisms associated with the disease, as well as virulence traits of Balamuthia that may be potential targets for therapeutic interventions and/or for the development of preventative measures.
Topics: Animals; Humans; Life Cycle Stages; Lobosea; Protozoan Infections
PubMed: 18625680
DOI: 10.1128/CMR.00056-07 -
Applied and Environmental Microbiology May 2005Balamuthia mandrillaris is a free-living ameba and an opportunistic agent of granulomatous encephalitis in humans and other mammalian species. Other free-living amebas,...
Balamuthia mandrillaris is a free-living ameba and an opportunistic agent of granulomatous encephalitis in humans and other mammalian species. Other free-living amebas, such as Acanthamoeba and Hartmannella, can provide a niche for intracellular survival of bacteria, including the causative agent of Legionnaires' disease, Legionella pneumophila. Infection of amebas by L. pneumophila enhances the bacterial infectivity for mammalian cells and lung tissues. Likewise, the pathogenicity of amebas may be enhanced when they host bacteria. So far, the colonization of B. mandrillaris by bacteria has not been convincingly shown. In this study, we investigated whether this ameba could host L. pneumophila bacteria. Our experiments showed that L. pneumophila could initiate uptake by B. mandrillaris and could replicate within the ameba about 4 to 5 log cycles from 24 to 72 h after infection. On the other hand, a dotA mutant, known to be unable to propagate in Acanthamoeba castellanii, also did not replicate within B. mandrillaris. Approaching completion of the intracellular cycle, L. pneumophila wild-type bacteria were able to destroy their ameboid hosts. Observations by light microscopy paralleled our quantitative data and revealed the rounding, collapse, clumping, and complete destruction of the infected amebas. Electron microscopic studies unveiled the replication of the bacteria in a compartment surrounded by a structure resembling rough endoplasmic reticulum. The course of intracellular infection, the degree of bacterial multiplication, and the ultrastructural features of a L. pneumophila-infected B. mandrillaris ameba resembled those described for other amebas hosting Legionella bacteria. We hence speculate that B. mandrillaris might serve as a host for bacteria in its natural environment.
Topics: Amoeba; Animals; Encephalitis; Legionella pneumophila; Opportunistic Infections
PubMed: 15870307
DOI: 10.1128/AEM.71.5.2244-2249.2005 -
Clinical Infectious Diseases : An... May 2019Balamuthia mandrillaris is a free-living ameba that causes rare, nearly always fatal disease in humans and animals worldwide. B. mandrillaris has been isolated from...
BACKGROUND
Balamuthia mandrillaris is a free-living ameba that causes rare, nearly always fatal disease in humans and animals worldwide. B. mandrillaris has been isolated from soil, dust, and water. Initial entry of Balamuthia into the body is likely via the skin or lungs. To date, only individual case reports and small case series have been published.
METHODS
The Centers for Disease Control and Prevention (CDC) maintains a free-living ameba (FLA) registry and laboratory. To be entered into the registry, a Balamuthia case must be laboratory-confirmed. Several sources were used to complete entries in the registry, including case report forms, CDC laboratory results, published case reports, and media information. SAS© version 9.3 software was used to calculate descriptive statistics and frequencies.
RESULTS
We identified 109 case reports of Balamuthia disease between 1974 and 2016. Most (99%) had encephalitis. The median age was 36 years (range 4 months to 91 years). Males accounted for 68% of the case patients. California had the highest number of case reports, followed by Texas and Arizona. Hispanics constituted 55% for those with documented ethnicity. Exposure to soil was commonly reported. Among those with a known outcome, 90% of patients died.
CONCLUSIONS
Balamuthia disease in the United States is characterized by a highly fatal encephalitis that affects patients of all ages. Hispanics were disproportionately affected. The southwest region of the United States reported the most cases. Clinician awareness of Balamuthia as a cause of encephalitis might lead to earlier diagnosis and initiation of treatment, resulting in better outcomes.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amebiasis; Balamuthia mandrillaris; Central Nervous System Protozoal Infections; Child; Child, Preschool; Female; Humans; Infant; Infectious Encephalitis; Male; Middle Aged; Registries; Sequence Analysis, DNA; United States; Young Adult
PubMed: 30239654
DOI: 10.1093/cid/ciy813 -
Parasite (Paris, France) 2021In this review, we focus on the sequenced genomes of the pathogens Naegleria fowleri, Acanthamoeba spp. and Balamuthia mandrillaris, and the remarkable discoveries... (Review)
Review
In this review, we focus on the sequenced genomes of the pathogens Naegleria fowleri, Acanthamoeba spp. and Balamuthia mandrillaris, and the remarkable discoveries regarding the pathogenicity and genetic information of these organisms, using techniques related to the various omics branches like genomics, transcriptomics, and proteomics. Currently, novel data produced through comparative genomics analyses and both differential gene and protein expression in these free-living amoebas have allowed for breakthroughs to identify genes unique to N. fowleri, genes with active transcriptional activity, and their differential expression in conditions of modified virulence. Furthermore, orthologous genes of the various nuclear genomes within the Naegleria and Acanthamoeba genera have been clustered. The proteome of B. mandrillaris has been reconstructed through transcriptome data, and its mitochondrial genome structure has been thoroughly described with a unique characteristic that has come to light: a type I intron with the capacity of interrupting genes through its self-splicing ribozymes activity. With the integration of data derived from the diverse omic sciences, there is a potential approximation that reflects the molecular complexity required for the identification of virulence factors, as well as crucial information regarding the comprehension of the molecular mechanisms with which these interact. Altogether, these breakthroughs could contribute to radical advances in both the fields of therapy design and medical diagnosis in the foreseeable future.
Topics: Acanthamoeba; Balamuthia mandrillaris; Genome, Protozoan; Genomics; Naegleria fowleri; Proteomics; Transcriptome; Virulence
PubMed: 33843581
DOI: 10.1051/parasite/2021033 -
Bioengineering (Basel, Switzerland) Jul 2022A spheroid is a cell aggregate in a three-dimensional context; thereby, it recapitulates the cellular architecture in human tissue. However, the utility of spheroids as...
A spheroid is a cell aggregate in a three-dimensional context; thereby, it recapitulates the cellular architecture in human tissue. However, the utility of spheroids as an assay for host-parasite interactions remains unexplored. This study demonstrates the potential use of neurospheroids for assessing the cytotoxicity of the life-threatening pathogenic amoeba . The neuroblastoma SH-SY5Y cells formed a spheroid in a hanging drop of culture medium. Cellular damage caused by trophozoites on human neuronal spheroids was observed using microscopic imaging and ATP detection. trophozoites rapidly caused a decrease in ATP production in the spheroid, leading to loss of neurospheroid integrity. Moreover, 3D confocal microscopy imaging revealed interactions between the trophozoites and SH-SY5Y neuronal cells in the outer layer of the neurospheroid. In conclusion, the neurospheroid allows the assessment of host cell damage in a simple and quantitative manner.
PubMed: 35877381
DOI: 10.3390/bioengineering9070330