Download MendeleyFrom Substrate to Fragments to Inhibitor ActiveIn VivoagainstStaphylococcus aureus.
Gelin, M., Paoletti, J., Nahori, M.A., Huteau, V., Leseigneur, C., Jouvion, G., Dugue, L., Clement, D., Pons, J.L., Assairi, L., Pochet, S., Labesse, G., Dussurget, O.(2020) ACS Infect Dis 6: 422-435
- PubMed: 32017533
- DOI: https://doi.org/10.1021/acsinfecdis.9b00368
- Primary Citation of Related Structures:
6RBO, 6RBP, 6RBQ, 6RBR, 6RBS, 6RBT, 6RBU, 6RBV, 6RBW, 6RBX, 6RBY, 6RBZ, 6RC0, 6RC1, 6RC2, 6RC3, 6RC4, 6RC5, 6RC6, 6RG6, 6RG7, 6RG8, 6RG9, 6RGA, 6RGB, 6RGC, 6RGD, 6RR2 - PubMed Abstract:
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.
Organizational Affiliation:
Centre de Biochimie Structurale, CNRS UMR 5048, INSERM U1054, Universit¨¦ Montpellier, 29 route de Navacelles, 34090 Montpellier, France.
