期刊
ACS INFECTIOUS DISEASES
卷 6, 期 3, 页码 422-435出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00368
关键词
adenosine derivative; bacterial NAD kinase; antibacterial compound; staphylococci; MRSA
资金
- Agence Nationale de la Recherche [ANR-06-BLAN-0324, ANR-11-EMM-0019, ANR-17-CE18-0011-02]
- Centre National de la Recherche Scientifique (CNRS), Institut National de la Santeet de la Recherche Medicale (INSERM), Institut Pasteur
- Institut Curie
- ANR [ANR-17-CE18-0011-02]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-01, Idex UP2019]
- EMBL-Grenoble [ID14-1, ID14-4, ID23-1, ID23-2, ID29, ID30B, ID30A1, ID30A3]
- Agence Nationale de la Recherche (ANR) [ANR-06-BLAN-0324, ANR-17-CE18-0011] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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