Discovery Of Vnrx-7145 (Vnrx-5236 Etzadroxil): An Orally Bioavailable Beta-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 beta-lactamase enzymes. The increasing emergence of beta-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 beta-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 beta-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.