DIAZABICYCLOOCTANE FUNCTIONALIZATION FOR INHIBITION OF -LACTAMASES FROM ENTEROBACTERIA

Flavie Bouchet (1) , Heiner Atze (2) , Matthieu Fonvielle (2) , Zainab Edoo (2) , Michel Arthur (2) , Mélanie Ethève-Quelquejeu (1) , Laura Iannazzo (1)

1 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
2 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

Second-generation-lactamase inhibitors containing a dia abic clooctane (DBO) scaffold restore the activit of-lactams against pathogenic bacteria, including those producing class A, C, and D en mes that are not susceptible to first-generation inhibitors containing a-lactam ring. Here, e report optimi ation of a s nthetic route to access tria ole-containing DBOs and biological evaluation of a series of 17 compounds for inhibition of five-lactamases representative of en mes found in pathogenic Gram-negative bacteria. A strong correlation (Spearman coefficient of 0.87; = 4.7 10-21) as observed bet een the inhibition efficac of purified-lactamases and the potentiation of-lactam antibacterial activit indicating that DBO functionali ation did not impair penetration. In comparison to reference DBOs, avibactam and relebactam, our compounds displa ed reduced efficac likel due to the absence of h drogen bonding ith a conserved asparagine residue at position 132. This as partiall compensated b additional interactions involving certain tria ole substituents.

Domaines: Chimie thérapeutique

Flavie Bouchet, Heiner Atze, Matthieu Fonvielle, Zainab Edoo, Michel Arthur, et al.. DIAZABICYCLOOCTANE FUNCTIONALIZATION FOR INHIBITION OF -LACTAMASES FROM ENTEROBACTERIA. Journal of Medicinal Chemistry, In press, ⟨10.1021/acs.jmedchem.9b02125⟩. ⟨hal-03646829v1⟩