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Jérémy Caburet

Rational conception of new NDM-1 inhibitors for antibiotic treatment by fragment approach

Published on 15 October 2021
Thesis presented October 15, 2021

Antibiotic resistance remains currently a major public health problem. One of the most problematic mechanisms of resistance is the enzymatic hydrolysis of antibiotics of the Beta-lactam family. The New-Delhi Metallo-Beta-lactamase-1 (NDM-1) is a protein with two zinc atoms in its active site. This enzyme can cleave a large part of Beta-lactams, even carbapenems which are the last line of antibiotic treatments in hospital. Since its discovery at the end of 2008, no inhibitor was marketed thus making NDM-1 a major target to fight antibiotic resistance. With that goal in mind, we elaborate a strategy based on a fragment approach using docking, organic synthesis and NMR screening evaluation to find new inhibitors of this enzyme. Initially, a virtual screening of 770,000 molecules allowed us to identify 25 fragments as potential hits for the inhibition of NDM-1. These fragments were synthesized and analyzed by Saturation Transfer Difference NMR experiments in presence of the protein. In parallel, a part of the library of the "Centre de Recherche et de Cancérologie de Lyon" (280 fragments) was also screened by NMR. A correlation between all results (virtual screening, NMR and bibliography) highlighted 48 hit fragments. In the next step, two of them have been chemically modulated: 2-hydroxyacetophenone and 8-hydroxyquinoline. We are particularly interested in the latter which was previously identified to bind with another bi-nuclear zinc enzyme. Synthetic methodologies have been developed to prepare molecules with this fragment. The newly synthetized structures will then be tested by bio-assays to carry out structure activity relationships in order to develop efficient inhibitors of NDM-1.

Antibiotic resistance, NDM-1 inhibitors, Fragment approach, Organic synthesis, Docking, NMR screening