From Substrate to Fragments to Inhibitor Active In Vivo against Staphylococcus aureus

Muriel Gelin (1) , Julie Paoletti (2) , Marie-Anne Nahori (3) , Valeŕie Huteau (2) , Clarisse Leseigneur (4, 5) , Greǵory Jouvion (6, 7, 8) , Laurence Dugué (2) , David Clément (2) , Jean-Luc Pons (1) , Liliane Assairi (9, 10) , Sylvie Pochet (2) , Gilles Labesse (1) , Olivier Dussurget (4, 5)

1 CBS - Centre de Biochimie Structurale [Montpellier]
2 Chimie et Biocatalyse
3 Toxines bactériennes - Bacterial Toxins
4 Yersinia
5 USPC - Université Sorbonne Paris Cité
6 Neuropathologie expérimentale - Experimental neuropathology
7 U933 - Maladies génétiques d'expression pédiatrique
8 CHU Trousseau [APHP]
9 Imagerie intégrative de la molécule à l'organisme
10 UP11 - Université Paris-Sud - Paris 11

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.

Mots clés: antibacterial compound; adenosine derivative; staphylococci; bacterial NAD kinase; MRSA

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire

Muriel Gelin, Julie Paoletti, Marie-Anne Nahori, Valeŕie Huteau, Clarisse Leseigneur, et al.. From Substrate to Fragments to Inhibitor Active In Vivo against Staphylococcus aureus. ACS Infectious Diseases, 2020, 6 (3), ⟨10.1021/acsinfecdis.9b00368⟩. ⟨hal-02573173⟩