In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii.
In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii.
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DOI：
10.3390/pathogens9090681
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发表时间：
2020-08-21
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;Escrig JI;Shing B;Debnath A
阿米巴角膜炎（AK）可发生在戴隐形眼镜的健康个体中，它是由自由生活的阿米巴阿米巴引起的角膜的疼痛、致盲感染。目前对AK的治疗依赖于氯己定、羟乙基磺酸丙脒和聚双胍的组合。然而，目前的治疗方案包括一种积极的消毒剂，在10%的情况下复发性感染。因此，开发有效和安全的药物是避免失明的关键未满足需求。阿米巴甾醇生物合成包括两个必需的酶HMG-CoA还原酶（HMGR）和甾醇14-脱甲基酶（CYP 51），我们早期发现了一种CYP 51抑制剂艾沙康唑，其表现出纳摩尔的抗A.卡氏滋养体在这项研究中，我们研究了耐受性良好的HMGR抑制剂的作用，并确定了匹伐他汀对三种不同临床株的A. castellanii。匹伐他汀的EC 50为0.5 - 1.9 µM，具体取决于菌株。匹伐他汀和艾沙康唑的组合是协同的，并且导致匹伐他汀的剂量减少2至9倍，艾沙康唑的剂量减少11至4000倍，以实现97%的生长抑制。匹伐他汀单独或与艾沙康唑联合使用，可能导致将其重新用于治疗阿米巴角膜炎。
Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful, blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, the current regimen includes an aggressive disinfectant and in 10% of cases recurrent infection ensues. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Acanthamoeba sterol biosynthesis includes two essential enzymes HMG-CoA reductase (HMGR) and sterol 14-demethylase (CYP51), and we earlier identified a CYP51 inhibitor isavuconazole that demonstrated nanomolar potency against A. castellanii trophozoites. In this study, we investigated the effect of well-tolerated HMGR inhibitors and identified pitavastatin that is active against trophozoites of three different clinical strains of A. castellanii. Pitavastatin demonstrated an EC50 of 0.5 to 1.9 µM, depending on strains. Combination of pitavastatin and isavuconazole is synergistic and led to 2- to 9-fold dose reduction for pitavastatin and 11- to 4000-fold dose reduction for isavuconazole to achieve 97% of growth inhibition. Pitavastatin, either alone or in combination with isavuconazole, may lead to repurposing for the treatment of Acanthamoeba keratitis.
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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：
4.6
作者：
Parihar, Suraj P.;Hartley, Mary-Anne;Brombacher, Frank
通讯作者：
Brombacher, Frank
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
DOI：
10.2147/dddt.s145545
发表时间：
2018
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Jenks JD;Salzer HJ;Prattes J;Krause R;Buchheidt D;Hoenigl M
通讯作者：
Hoenigl M
影响因子：
4.1
作者：
Illingworth, CD;Cook, SD;Easty, DL
通讯作者：
Easty, DL