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Structure-based design of NAD+ analogues targeting bacterial NAD kinases, promising targets for new antibiotics

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Rahimova, Rahila | Nogaret, Pauline | Huteau, Valérie | Leseigneur, Clarisse | Gelin, Muriel | Clément, David, A. | Dussurget, Olivier | Labesse, Gilles | Pochet, Sylvie, S. | Blanc-Potard, Anne-Béatrice | Lionne, Corinne

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International audience. Multi-drug resistance is a major public health problem that requires the urgent development of new antibiotics and therefore the identification of novel bacterial targets. The activity of nicotinamide adenine dinucleotide kinase, NADK, is essential in all bacteria tested so far, including many human pathogens that display antibiotic resistance leading to failure of current treatments. Inhibiting NADK is therefore a promising and innovative antibacterial strategy since there is currently no drug on the market targeting this enzyme. Through a drug design approach based on substrate-derived fragments, we have recently developed NAD+-competitive inhibitors of NADKs, which displayed in vivo activity against Staphylococcus aureus or Pseudomonas aeruginosa in animal models of infection [1-3].Funding and supports: Agence Nationale de la Recherche (ANR-17-CE18-0011-02), Institut Pasteur, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Montpellier.References: [1] Clément DA, Leseigneur C, Gelin M, Coelho D, Huteau V, Lionne C, Labesse G, Dussurget O, Pochet S (2020) New chemical probe targeting bacterial NAD kinase. Molecules. doi: 10.3390/molecules25214893.[2] Gelin M, Paoletti J, Nahori MA, Huteau V, Leseigneur C, Jouvion G, Dugué L, Clément D, Pons JL, Assairi L, Pochet S, Labesse G, Dussurget O (2020) From substrate to fragments to inhibitor active in vivo against Staphylococcus aureus. ACS Infect Dis. doi: 10.1021/acsinfecdis.9b00368.[3] Rahimova R, Nogaret P, HuteauV, Gelin M, Clément D, Labesse G, Pochet S, Blanc-Potard A, Lionne C (2022) Structure-based design, synthesis and biological evaluation of a NAD+ analogue targeting Pseudomonas aeruginosa NAD kinase. In Preparation.

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