In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against Naegleria fowleri.
In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against Naegleria fowleri.
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Farnesylysylansferase抑制剂的体外评估及其与Naegleria Fowleri相对于Naegleria Fowleri的3-羟基-3-甲基 - 核酸-COA还原酶抑制剂的影响。
DOI：
10.3390/pathogens9090689
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发表时间：
2020-08-22
期刊：
影响因子：
--
通讯作者：
Debnath A
中科院分区：
文献类型：
--
作者：
Hahn HJ;Debnath A
自由生活的福氏耐格里阿米巴在儿童中引起快速致命的感染原发性阿米巴脑膜脑炎（PAM）。治疗PAM的首选药物是阿朴霉素B，但很少有接受阿朴霉素B治疗的患者在PAM中存活。因此，有效药物的开发是一个关键的未满足的需求。我们发现，FDA批准的匹伐他汀（一种参与甲羟戊酸途径的HMG Co-A还原酶抑制剂B对N. fowleri滋养体N. Fowleri含有编码蛋白法尼基转移酶（FT）的基因，法尼基转移酶是甲羟戊酸途径衍生产物的最后一种常见酶。在这里，我们表明，临床先进的FT抑制剂洛那法尼是积极的对不同菌株的N。fowleri的EC 50范围为1.5至9.2 µM。不同比例的洛那法尼和匹伐他汀的组合导致滋养体的95%生长抑制，并且该组合实现了洛那法尼约2至28倍的剂量降低和匹伐他汀约5至30倍的剂量降低。当用1.7 µM洛那法尼和匹伐他汀联合处理滋养体48 h时，未发现具有正常形态的滋养体。洛那法尼和匹伐他汀的组合可能有助于开发用于治疗PAM的新药物方案。
Free-living amoeba Naegleria fowleri 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 N. fowleri trophozoites. The genome of N. fowleri 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 N. fowleri with EC50 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.
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影响因子：
4.8
作者：
Chakrabarti, D;Da Silva, T;Allen, CM
通讯作者：
Allen, CM
影响因子：
3.8
作者：
Debnath, Anjan;Calvet, Claudia M;Podust, Larissa M
通讯作者：
Podust, Larissa M
影响因子：
5.2
作者：
Debnath A;Nelson AT;Silva-Olivares A;Shibayama M;Siegel D;McKerrow JH
通讯作者：
McKerrow JH
影响因子：
4.1
作者：
Illingworth, CD;Cook, SD;Easty, DL
通讯作者：
Easty, DL
影响因子：
4.8
作者：
Kumagai, M;Makioka, A;Nozaki, T
通讯作者：
Nozaki, T