In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i>
Free-living amoeba <i>Naegleria fowleri</i> causes a rapidly fatal infection primary amebic meningoencephalitis (PAM) in children. The drug of choice in treating PAM is amphotericin B, but very few patients treated with amphotericin B have survived PAM. Therefore, development of efficien...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/9/9/689 |
| _version_ | 1797556173243678720 |
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| author | Hye Jee Hahn Anjan Debnath |
| author_facet | Hye Jee Hahn Anjan Debnath |
| author_sort | Hye Jee Hahn |
| collection | DOAJ |
| description | Free-living amoeba <i>Naegleria fowleri</i> causes a rapidly fatal infection primary amebic meningoencephalitis (PAM) in children. The drug of choice in treating PAM is amphotericin B, but very few patients treated with amphotericin B have survived PAM. Therefore, development of efficient drugs is a critical unmet need. We identified that the FDA-approved pitavastatin, an inhibitor of HMG Co-A reductase involved in the mevalonate pathway, was equipotent to amphotericin B against <i>N. fowleri</i> trophozoites. The genome of <i>N. fowleri</i> contains a gene encoding protein farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway. Here, we show that a clinically advanced FT inhibitor lonafarnib is active against different strains of <i>N. fowleri</i> with EC<sub>50</sub> ranging from 1.5 to 9.2 µM. A combination of lonafarnib and pitavastatin at different ratios led to 95% growth inhibition of trophozoites and the combination achieved a dose reduction of about 2- to 28-fold for lonafarnib and 5- to 30-fold for pitavastatin. No trophozoite with normal morphology was found when trophozoites were treated for 48 h with a combination of 1.7 µM each of lonafarnib and pitavastatin. Combination of lonafarnib and pitavastatin may contribute to the development of a new drug regimen for the treatment of PAM. |
| first_indexed | 2024-03-10T16:59:08Z |
| format | Article |
| id | doaj.art-9a73d43d57514084ac5fbea6a13336ad |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-10T16:59:08Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-9a73d43d57514084ac5fbea6a13336ad2023-11-20T11:02:40ZengMDPI AGPathogens2076-08172020-08-019968910.3390/pathogens9090689In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i>Hye Jee Hahn0Anjan Debnath1Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USACenter for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USAFree-living amoeba <i>Naegleria fowleri</i> causes a rapidly fatal infection primary amebic meningoencephalitis (PAM) in children. The drug of choice in treating PAM is amphotericin B, but very few patients treated with amphotericin B have survived PAM. Therefore, development of efficient drugs is a critical unmet need. We identified that the FDA-approved pitavastatin, an inhibitor of HMG Co-A reductase involved in the mevalonate pathway, was equipotent to amphotericin B against <i>N. fowleri</i> trophozoites. The genome of <i>N. fowleri</i> contains a gene encoding protein farnesyltransferase (FT), the last common enzyme for products derived from the mevalonate pathway. Here, we show that a clinically advanced FT inhibitor lonafarnib is active against different strains of <i>N. fowleri</i> with EC<sub>50</sub> ranging from 1.5 to 9.2 µM. A combination of lonafarnib and pitavastatin at different ratios led to 95% growth inhibition of trophozoites and the combination achieved a dose reduction of about 2- to 28-fold for lonafarnib and 5- to 30-fold for pitavastatin. No trophozoite with normal morphology was found when trophozoites were treated for 48 h with a combination of 1.7 µM each of lonafarnib and pitavastatin. Combination of lonafarnib and pitavastatin may contribute to the development of a new drug regimen for the treatment of PAM.https://www.mdpi.com/2076-0817/9/9/689<i>Naegleria fowleri</i>free-living amoebaprimary amoebic meningoencephalitislonafarnibpitavastatinfarnesyltransferase |
| spellingShingle | Hye Jee Hahn Anjan Debnath In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i> Pathogens <i>Naegleria fowleri</i> free-living amoeba primary amoebic meningoencephalitis lonafarnib pitavastatin farnesyltransferase |
| title | In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i> |
| title_full | In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i> |
| title_fullStr | In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i> |
| title_full_unstemmed | In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i> |
| title_short | In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against <i>Naegleria fowleri</i> |
| title_sort | in vitro evaluation of farnesyltransferase inhibitor and its effect in combination with 3 hydroxy 3 methyl glutaryl coa reductase inhibitor against i naegleria fowleri i |
| topic | <i>Naegleria fowleri</i> free-living amoeba primary amoebic meningoencephalitis lonafarnib pitavastatin farnesyltransferase |
| url | https://www.mdpi.com/2076-0817/9/9/689 |
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