APX001A / APX001和其他Gwt1抑制剂对隐球菌的体外和体内评估。,Antimicrobial Agents and Chemotherapy

当前位置： X-MOL 学术 › Antimicrob. Agents Chemother. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

APX001A / APX001和其他Gwt1抑制剂对隐球菌的体外和体内评估。
Antimicrobial Agents and Chemotherapy ( IF 4.1 ) Pub Date : 2018-07-27 , DOI: 10.1128/aac.00523-18
Karen Joy Shaw ₁ , Wiley A Schell ₂ , Jonathan Covel ₃ , Gisele Duboc ₂ , C Giamberardino ₂ , Mili Kapoor ₃ , Molly Moloney ₃ , Quinlyn A Soltow ₃ , Jennifer L Tenor ₂ , Dena L Toffaletti ₂ , Michael Trzoss ₃ , Peter Webb ₃ , John R Perfect ₂

Affiliation

隐球菌性脑膜炎（CM）主要由新隐球菌引起，如果不加以治疗，则会致命。治疗选择有限，尤其是在资源贫乏的地理区域，尽管采用了目前的治疗方法，死亡率仍然很高。在这里，我们评估了几种化合物的体外和体内活性，包括APX001A及其前体药物APX001，这些化合物目前正在临床中用于治疗侵袭性真菌感染。这些化合物靶向在真菌中定位糖基磷脂酰肌醇（GPI）锚定的细胞壁甘露糖蛋白所需的保守Gwt1酶。Gwt1抑制剂对新孢子虫和C. gattii APX001A和APX2020的MIC值较低，范围从0.004μg/ ml至0.5μg/ ml，表现出与氟康唑的体外协同作用（分数抑制浓度指数为0。两者均为37）。在CM模型中，APX001和氟康唑分别单独减轻脑组织中的真菌负荷（分别为0.78和1.04 log10 CFU / g），而组合导致脑组织的3.52 log10 CFU / g减少。还观察到另一种Gwt1抑制剂前药APX2096的功效，通过减少脑和肺组织的真菌负荷来衡量，其中剂量依赖性真菌负荷的减少范围为5.91至1.79 log10 CFU / g肺组织，而从7.00和0.92 log10 CFU / g脑组织，表示在较高剂量下肺和脑组织几乎完全或完全灭菌。这些数据支持这种新型的抗真菌药物用于CM的进一步临床评估。分别为04 log10 CFU / g），而该组合可减少3.52 log10 CFU / g脑组织。还通过另一种Gwt1抑制剂前药APX2096观察到了通过减少脑和肺组织真菌负担来衡量的功效，其中剂量依赖性真菌负担的减少幅度为5.91至1.79 log10 CFU / g肺组织，而从7.00和0.92 log10 CFU / g脑组织，表示在较高剂量下肺和脑组织几乎完全或完全灭菌。这些数据支持这种新型的抗真菌药物用于CM的进一步临床评估。分别为04 log10 CFU / g），而该组合可减少3.52 log10 CFU / g脑组织。还观察到另一种Gwt1抑制剂前药APX2096的功效，通过减少脑和肺组织的真菌负荷来衡量，其中剂量依赖性真菌负荷的减少范围为5.91至1.79 log10 CFU / g肺组织，而从7.00和0.92 log10 CFU / g脑组织，表示在较高剂量下肺和脑组织几乎完全或完全灭菌。这些数据支持这种新型的抗真菌药物用于CM的进一步临床评估。还观察到了另一种Gwt1抑制剂前药APX2096，其中真菌负荷的剂量依赖性降低范围从5.91到1.79 log10 CFU / g肺组织，从7.00和0.92 log10 CFU / g脑组织，代表几乎完全或完全灭菌较高剂量的肺和脑组织。这些数据支持这种新型的抗真菌药物用于CM的进一步临床评估。还观察到了另一种Gwt1抑制剂前药APX2096，其中真菌负荷的剂量依赖性降低范围从5.91到1.79 log10 CFU / g肺组织，从7.00和0.92 log10 CFU / g脑组织，代表几乎完全或完全灭菌较高剂量的肺和脑组织。这些数据支持这种新型的抗真菌药物用于CM的进一步临床评估。

"点击查看英文标题和摘要"

In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus.

Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated the in vitro and in vivo activity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against both C. neoformans and C. gattii APX001A and APX2020 demonstrated in vitro synergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10 CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10 CFU/g lung tissue and from 7.00 and 0.92 log10 CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南