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：

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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β-内酰胺的金黄色葡萄球菌的抗生素佐剂。

随着抗生素抗性的提高，需要诸如抗生素佐剂的策略以保存已经建立的抗生素。作为β-内酰胺类抗生素佐剂的靶标，一类称为青霉素结合蛋白和丝氨酸/苏氨酸激酶相关（PASTA）激酶的细菌激酶引起了人们的关注。在这里，我们报告吡唑并哒嗪GW779439X通过抑制PASTA激酶Stk1使耐甲氧西林的金黄色葡萄球菌（MRSA）对各种β-内酰胺敏感。GW779439X增强了针对多种MRSA和MSSA分离物的β-内酰胺活性，包括对头孢洛林具有耐药性的分离物对头孢洛林的敏化作用。使用计算机模拟来指导GW779439X衍生物的合成。GW779439X'的存在与发展方向 甲基哌嗪部分对于强大的生化和微生物活性至关重要。综上所述，我们的数据为开发吡唑并哒嗪作为选择性的Stk1抑制剂提供了概念验证，该抑制剂可跨金黄色葡萄球菌分离物起作用。