Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia

Publication date: Available online 22 October 2019Source: International Journal for Parasitology: Drugs and Drug ResistanceAuthor(s): Monica M. Kangussu-Marcolino, Gretchen M. Ehrenkaufer, Emily Chen, Anjan Debnath, Upinder SinghAbstractThe free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify central nervous system (CNS)-permeable anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on CNS penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. ...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research

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Acanthamoeba is well known to produce a blinding keratitis and serious brain infection known as encephalitis. Effective treatment is problematic, and can continue up to a year, and even then, recurrence can ensue...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
CONCLUSIONS: The scarcity of the studies trying to understand the compatibility as well as the exact mechanisms by which NDDS might be serving to enter the CNS infected by parasites opens new possibilities for further exploratory projects. There is an urgent need for new investments and motivations in the area of nanotechnology applied to the control of parasitic infectious diseases worldwide. PMID: 31612822 [PubMed - as supplied by publisher]
Source: Current Pharmaceutical Design - Category: Drugs & Pharmacology Authors: Tags: Curr Pharm Des Source Type: research
Pathogenic protozoans use extracellular vesicles (EVs) for intercellular communication and host manipulation. Acanthamoeba castellanii is a free-living protozoan that may cause severe keratitis and fatal granulom...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
Authors: Bunsuwansakul C, Mahboob T, Hounkong K, Laohaprapanon S, Chitapornpan S, Jawjit S, Yasiri A, Barusrux S, Bunluepuech K, Sawangjaroen N, Salibay CC, Kaewjai C, Pereira ML, Nissapatorn V Abstract Acanthamoeba, one of free-living amoebae (FLA), remains a high risk of direct contact with this protozoan parasite which is ubiquitous in nature and man-made environment. This pathogenic FLA can cause sight-threatening amoebic keratitis (AK) and fatal granulomatous amoebic encephalitis (GAE) though these cases may not commonly be reported in our clinical settings. Acanthamoeba has been detected from different enviro...
Source: Korean Journal of Parasitology - Category: Parasitology Tags: Korean J Parasitol Source Type: research
s Orozco The epithelium represents the first and most extensive line of defence against pathogens, toxins and pollutant agents in humans. In general, pathogens have developed strategies to overcome this barrier and use it as an entrance to the organism. Entamoeba histolytica, Naegleria fowleri and Acanthamoeba spp. are amoebae mainly responsible for intestinal dysentery, meningoencephalitis and keratitis, respectively. These amoebae cause significant morbidity and mortality rates. Thus, the identification, characterization and validation of molecules participating in host-parasite interactions can provide attractive...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Review Source Type: research
CONCLUSIONS: Recent studies have shown that many natural compounds have high anti-parasitic properties and low toxicity. Our research team hopes that the information provided in present systematic review can improve of new experimental and clinical trials and herbal combination therapy.Further studies are needed to understand the molecular mechanisms in the anti-amoebic reactions of plant species and ocular toxicity of extracts in animal models. PMID: 31322072 [PubMed - as supplied by publisher]
Source: Infectious Disorders Drug Targets - Category: Infectious Diseases Authors: Tags: Infect Disord Drug Targets Source Type: research
Nick Humphreys, of Shropshire, noticed a scratch on his right eye in January 2018. By March, he had gone blind because of Acanthamoeba keratitis, a parasitic infection.
Source: the Mail online | Health - Category: Consumer Health News Source Type: news
The iron superoxide dismutase found in the pathogenic amoeba Acanthamoeba castellanii (AcFeSOD) may play essential roles in the survival of the parasite, not only by protecting it from endogenous oxidative stress but also by detoxifying oxidative killing of the parasite by host immune effector cells. The AcFeSOD protein was expressed in a stable form using an Escherichia coli expression system and was crystallized by the microbatch and hanging-drop vapour-diffusion methods. The structure was determined to 2.33   Å resolution from a single AcFeSOD crystal. The crystal belonged to the hexagonal space group P61 and co...
Source: Acta Crystallographica Section F - Category: Biochemistry Authors: Tags: iron superoxide dismutase Acanthamoeba castellanii research communications Source Type: research
Species of Acanthamoeba are facultative pathogens which can cause sight threatening Acanthamoeba keratitis and a rare but deadly brain infection, granulomatous amoebic encephalitis. Due to conversion of Acanthamo...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
This study was aimed to evaluate the activity of the Medicines for Malaria Venture (MMV) compounds against the trophozoite stage of Acanthamoeba castellanii Neff. Sixteen compounds showed ≥ 90% inhibition of parasite growth in the initial screen (10 μM). Those set were further evaluated to determine the inhibitor concentration that inhibit the 50% of the initial population and cytotoxicity against murine macrophages. Among the compounds included in the pathogen box, pentamidine and posaconazole were the most effective against this parasite with an of IC50 of 0.567 ± 0.04 and 0.630 ± 0.11, respectively. ...
Source: Experimental Parasitology - Category: Parasitology Authors: Tags: Exp Parasitol Source Type: research
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