6vhs

Publication Abstract from PubMed

Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward beta-lactam antibiotics. The hydrolytic enzymes called beta-lactamases are responsible for a large proportion of the resistance phenotype. beta-Lactamase inhibitors (BLIs) can be administered in combination with beta-lactam antibiotics to negate the action of the beta-lactamases, thereby restoring activity of the beta-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) beta-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon-carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine beta-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.

Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine beta-Lactamases.,Durand-Reville TF, Comita-Prevoir J, Zhang J, Wu X, May-Dracka TL, Romero JAC, Wu F, Chen A, Shapiro AB, Carter NM, McLeod SM, Giacobbe RA, Verheijen JC, Lahiri SD, Sacco MD, Chen Y, O'Donnell JP, Miller AA, Mueller JP, Tommasi RA J Med Chem. 2020 Jul 24. doi: 10.1021/acs.jmedchem.0c00579. PMID:32658473^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.