Hahn Hye Jee, Debnath Anjan
Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Pathogens. 2020 Aug 22;9(9):689. doi: 10.3390/pathogens9090689.
Free-living amoeba 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 trophozoites. The genome of 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 with EC 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.
自由生活阿米巴可在儿童中引发一种迅速致命的感染——原发性阿米巴脑膜脑炎（PAM）。治疗PAM的首选药物是两性霉素B，但接受两性霉素B治疗的患者中很少有能从PAM中存活下来的。因此，开发有效的药物是一项关键的未满足需求。我们发现，美国食品药品监督管理局（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）对滋养体的效力与两性霉素B相当。[某种生物]的基因组包含一个编码蛋白质法尼基转移酶（FT）的基因，该酶是甲羟戊酸途径衍生产物的最后一种共同酶。在此，我们表明临床进展期的FT抑制剂洛那法尼对不同菌株的[某种生物]具有活性，其半数效应浓度（EC）范围为1.5至9.2 μM。不同比例的洛那法尼和匹伐他汀联合使用可导致滋养体生长抑制95%，且该联合用药使洛那法尼的剂量降低了约2至28倍，使匹伐他汀的剂量降低了5至30倍。当用1.7 μM的洛那法尼和匹伐他汀联合处理滋养体48小时后，未发现形态正常的滋养体。洛那法尼和匹伐他汀的联合使用可能有助于开发一种治疗PAM的新药物方案。
