GW779439X and Its Pyrazolopyridazine Derivatives Inhibit the Serine/Threonine Kinase Stk1 and Act As Antibiotic Adjuvants against β-Lactam-Resistant Staphylococcus aureus.,ACS Infectious Diseases

当前位置： X-MOL 学术 › ACS Infect. Dis. › 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.)

GW779439X and Its Pyrazolopyridazine Derivatives Inhibit the Serine/Threonine Kinase Stk1 and Act As Antibiotic Adjuvants against β-Lactam-Resistant Staphylococcus aureus.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-08-15 , DOI: 10.1021/acsinfecdis.8b00136
Adam J Schaenzer _{1,

2} , Nathan Wlodarchak _{1,

2} , David H Drewry ₃ , William J Zuercher ₃ , Warren E Rose _{2,

4} , Carla A Ferrer ₃ , John-Demian Sauer ₁ , Rob Striker _{1,

2,

5}

Affiliation

As antibiotic resistance rises, there is a need for strategies such as antibiotic adjuvants to conserve already-established antibiotics. A family of bacterial kinases known as the penicillin-binding-protein and serine/threonine kinase-associated (PASTA) kinases has attracted attention as targets for antibiotic adjuvants for β-lactams. Here, we report that the pyrazolopyridazine GW779439X sensitizes methicillin-resistant Staphylococcus aureus (MRSA) to various β-lactams through inhibition of the PASTA kinase Stk1. GW779439X potentiates β-lactam activity against multiple MRSA and MSSA isolates, including the sensitization of a ceftaroline-resistant isolate to ceftaroline. In silico modeling was used to guide the synthesis of GW779439X derivatives. The presence and orientation of GW779439X's methylpiperazine moiety was crucial for robust biochemical and microbiologic activity. Taken together, our data provide a proof of concept for developing the pyrazolopyridazines as selective Stk1 inhibitors which act across S. aureus isolates.

中文翻译：

GW779439X 及其吡唑并哒嗪衍生物抑制丝氨酸/苏氨酸激酶 Stk1，并作为抗生素佐剂对抗 β-内酰胺耐药金黄色葡萄球菌。

随着抗生素耐药性的增加，需要采取抗生素佐剂等策略来保护现有的抗生素。被称为青霉素结合蛋白和丝氨酸/苏氨酸激酶相关 (PASTA) 激酶的细菌激酶家族作为 β-内酰胺抗生素佐剂的靶标引起了人们的关注。在此，我们报道吡唑并哒嗪 GW779439X 通过抑制 PASTA 激酶 Stk1 使耐甲氧西林金黄色葡萄球菌 (MRSA) 对各种 β-内酰胺类药物敏感。 GW779439X 增强针对多种 MRSA 和 MSSA 分离株的 β-内酰胺活性，包括头孢洛林耐药分离株对头孢洛林的敏感性。使用计算机模拟来指导 GW779439X 衍生物的合成。 GW779439X 的甲基哌嗪部分的存在和方向对于强大的生化和微生物活性至关重要。总而言之，我们的数据为开发吡唑并哒嗪作为选择性 Stk1 抑制剂（作用于金黄色葡萄球菌分离株）提供了概念证明。

更新日期：2018-07-30

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