Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β‑Lactamases

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