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 spp. are cosmopolitan protozoans that cause infections in the brain, as well as extracerebral infections in the cornea, lungs and skin. Little is known about the mechanisms of the immunological respo...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
The encystation of Acanthamoeba leads to the development of resilient cysts from vegetative trophozoites. This process is essential for the survival of parasites under unfavorable conditions. Previous studies hav...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
Abstract Acanthamoeba spp. are free living amoeba (FLA) which are widely distributed in nature. They are opportunistic parasites and can cause severe infections to the eye, skin and central nervous system. The advances in drug discovery and modifications in the chemotherapeutic agents have shown little improvement in morbidity and mortality rates associated with Acanthamoeba infections. The mechanism-based process of drug discovery depends on the molecular drug targets present in the signaling pathways in the genome. Synthetic libraries provide a platform for broad spectrum of activities due to their desired struc...
Source: Acta Tropica - Category: Infectious Diseases Authors: Tags: Acta Trop Source Type: research
Abstract Free-living amoebae (FLA) including Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris are among the many waterborne parasites. There is not much known about the possible FLA contamination of the irrigation resources watering crops and agricultural lands in this country. Forty-five water samples were collected from water canals used for irrigation of farmlands and tested for the presence of pathogenic FLA using morphological and molecular-based methodology. The ITS region of Naegleria species was sequenced and a phylogenetic tree was generated to confirm the genetic associations and taxonom...
Source: Environmental Science and Pollution Research International - Category: Environmental Health Authors: Tags: Environ Sci Pollut Res Int Source Type: research
Authors: Mitsuwan W, Bunsuwansakul C, Leonard TE, Laohaprapanon S, Hounkong K, Bunluepuech K, Chalermpol K, Mahboob T, Sumudi Raju C, Dhobi M, Pereira ML, Mohammad N, Wiart C, Siyadatpanah A, Norouzi R, Nissapatorn V Abstract Curcuma longa (C. longa) rhizome extract has been traditionally used to treat many infections. Curcumin, a pure compound isolated from the plant, has been documented to possess a wide spectrum of pharmacological effects. The present study aimed to investigate the effects of Thai medicinal plant extracts including C. longa extract and Curcumin on Acanthamoeba triangularis, a causative agent of ...
Source: Pathogens and Global Health - Category: International Medicine & Public Health Tags: Pathog Glob Health Source Type: research
CONCLUSION: These extracts are not promising candidates for further medicine development on acanthamoebiasis. Nonetheless, further researches are necessary to clarify effective fractions of seed and leaf extracts of R. obtusifolius and their mechanisms of action. PMID: 32321413 [PubMed - as supplied by publisher]
Source: Infectious Disorders Drug Targets - Category: Infectious Diseases Authors: Tags: Infect Disord Drug Targets Source Type: research
This study demonstrated that the swimming pools and hot tub water in Qazvin province were contaminated with Acanthamoeba and Naegleria species. PMID: 32300097 [PubMed - in process]
Source: Journal of Water and Health - Category: Environmental Health Tags: J Water Health Source Type: research
by Gretchen Ehrenkaufer, Pengyang Li, Erin E. Stebbins, Monica M. Kangussu-Marcolino, Anjan Debnath, Corin V. White, Matthew S. Moser, Joseph DeRisi, Jolyn Gisselberg, Ellen Yeh, Steven C. Wang, Ana Hervella Company, Ludovica Monti, Conor R. Caffrey, Christopher D. Huston, Bo Wang, Upinder Singh Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Acanthamoeba spp. are ubiquitous pathogens which cause granulomatous amoebic encephalitis and disseminated infection. Moreover, Acanthamoeba spp. infection of the cornea leads to Acanthamoeba keratitis. Our previ...
Source: Parasites and Vectors - Category: Microbiology Authors: Tags: Research Source Type: research
AbstractThe present study evaluated the in vitro efficacy of miltefosine against cysts ofAcanthamoeba spp. belonging to genotypes T3, T4 and T5. Each genotype was incubated with miltefosine at the concentration of 2.42, 4.84, 9.68, 19.36, 38.72 and 77.44  mM for different periods; 1, 3, 5, 7 d at 37 °C. The viability was assessed by staining with 0.4% trypan blue and culturing on NNA medium at 30 °C for 1 month. The results showed 100% eradication of cyst stage of all concentrations, but exhibited a different degree of activity against differe nt genotypes. The MCC of 38.72 mM could kill ge...
Source: Journal of Parasitic Diseases - Category: Parasitology Source Type: research
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