Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine ?-Lactamases.

ABSTRACT: Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward ?-lactam antibiotics. The hydrolytic enzymes called ?-lactamases are responsible for a large proportion of the resistance phenotype. ?-Lactamase inhibitors (BLIs) can be administered in combination with ?-lactam antibiotics to negate the action of the ?-lactamases, thereby restoring activity of the ?-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) ?-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 ?-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.

SUBMITTER: Durand-Reville TF 

PROVIDER: S-EPMC7927146 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature