Antibiotic resistance is a worldwide threat due to the decreasing supply of new antimicrobials. Novel targets and innovative strategies are urgently needed to generate pathbreaking drug compounds. NAD kinase (NADK) is essential for growth in most bacteria, as it supports critical metabolic pathways. Here, we report the discovery of a new class of antibacterials that targets bacterial NADK. We generated a series of small synthetic adenine derivatives to screen those harboring promising substituents in order to guide efficient fragment linking. This led to NKI1, a new lead compound inhibiting NADK that showed in vitro bactericidal activity against Staphylococcus aureus. In a murine model of infection, NKI1 restricted survival of the bacteria, including methicillin-resistant S. aureus. Collectively, these findings identify bacterial NADK as a potential drug target and NKI1 as a lead compound in the treatment of staphylococcal infections.

中文翻译：

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从底物到片段再到抗金黄色葡萄球菌的活性抑制剂。

由于新抗菌素供应的减少，对抗生素的耐药性已成为全球性的威胁。迫切需要新颖的目标和创新的策略来产生突破性的药物化合物。NAD激酶（NADK）对大多数细菌的生长至关重要，因为它支持关键的代谢途径。在这里，我们报告了针对细菌NADK的一类新型抗菌剂的发现。我们生成了一系列小的合成腺嘌呤衍生物，以筛选那些具有前途的取代基，以指导有效的片段连接。这导致了NKI1，这是一种新的抑制NADK的先导化合物，该化合物对金黄色葡萄球菌具有体外杀菌活性。在鼠类感染模型中，NKI1限制了细菌的存活，包括耐甲氧西林的金黄色葡萄球菌。总的来说，