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
The 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 d...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320719301022 |
| _version_ | 1828382448011968512 |
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| author | Monica M. Kangussu-Marcolino Gretchen M. Ehrenkaufer Emily Chen Anjan Debnath Upinder Singh |
| author_facet | Monica M. Kangussu-Marcolino Gretchen M. Ehrenkaufer Emily Chen Anjan Debnath Upinder Singh |
| author_sort | Monica M. Kangussu-Marcolino |
| collection | DOAJ |
| description | The 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 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 central nervous system (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. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis. Keywords: Naegleria, Acanthamoeba, Balamuthia, ReFRAME library, CNS infection, Drug screening |
| first_indexed | 2024-12-10T04:32:54Z |
| format | Article |
| id | doaj.art-246cf7eb190844069f7ed6ba46f4fff9 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-10T04:32:54Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-246cf7eb190844069f7ed6ba46f4fff92022-12-22T02:02:06ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072019-12-01118094Identification 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 BalamuthiaMonica M. Kangussu-Marcolino0Gretchen M. Ehrenkaufer1Emily Chen2Anjan Debnath3Upinder Singh4Division of Infectious Diseases, Department of Internal Medicine, Stanford University, Grant Building, S-143, 300 Pasteur Drive, Stanford, CA, 94305, USADivision of Infectious Diseases, Department of Internal Medicine, Stanford University, Grant Building, S-143, 300 Pasteur Drive, Stanford, CA, 94305, USAuHTS Laboratory Rm 101, 11119 N Torrey Pines Rd. Calibr, A Division of the Scripps Research Institute, La Jolla, CA, 92037, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, USADivision of Infectious Diseases, Department of Internal Medicine, Stanford University, Grant Building, S-143, 300 Pasteur Drive, Stanford, CA, 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA, 94305, USA; Corresponding author. S-143 Grant Building, 300 Pasteur Drive, Stanford, CA, 94305, USA.The 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 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 central nervous system (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. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis. Keywords: Naegleria, Acanthamoeba, Balamuthia, ReFRAME library, CNS infection, Drug screeninghttp://www.sciencedirect.com/science/article/pii/S2211320719301022 |
| spellingShingle | Monica M. Kangussu-Marcolino Gretchen M. Ehrenkaufer Emily Chen Anjan Debnath Upinder Singh 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 International Journal for Parasitology: Drugs and Drug Resistance |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.sciencedirect.com/science/article/pii/S2211320719301022 |
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