Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β‑Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes

A major
antimicrobial resistance mechanism in Gram-negative bacteria
is the production of β-lactamase enzymes. The increasing emergence
of β-lactamase-producing multi-drug-resistant “superbugs”
has resulted in increases in costly hospital Emergency Department
(ED) visits and hospitalizations due to the requirement for parenteral
antibiotic therapy for infections caused by these difficult-to-treat
bacteria. To address the lack of outpatient treatment, we initiated
an iterative program combining medicinal chemistry, biochemical testing,
microbiological profiling, and evaluation of oral pharmacokinetics.
Lead optimization focusing on multiple smaller, more lipophilic active
compounds, followed by an exploration of oral bioavailability of a
variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236
etzadroxil), the prodrug of the boronic acid-containing β-lactamase
inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored
the activity of the oral cephalosporin antibiotic ceftibuten against
Enterobacterales expressing Ambler class A extended-spectrum β-lactamases,
class A carbapenemases, class C cephalosporinases, and class D oxacillinases.