TY - JOUR
T1 - Discovery of VNRX-7145 (VNRX-5236 Etzadroxil)
T2 - An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes
AU - Trout, Robert E.
AU - Zulli, Allison
AU - Mesaros, Eugen
AU - Jackson, Randy W.
AU - Boyd, Steven
AU - Liu, Bin
AU - Hamrick, Jodie
AU - Daigle, Denis
AU - Chatwin, Cassandra L.
AU - John, Kaitlyn
AU - McLaughlin, Lisa
AU - Cusick, Susan M.
AU - Weiss, William J.
AU - Pulse, Mark E.
AU - Pevear, Daniel C.
AU - Moeck, Greg
AU - Xerri, Luigi
AU - Burns, Christopher J.
N1 - Funding Information:
This project has been funded in whole or in part from the National Institute for Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract no. HHSN272201600029C and grant nos. R44AI109879, R01AI089512, R01AI111539, and R43AI109879.
Publisher Copyright:
© 2021 American Chemical Society
PY - 2021/7/22
Y1 - 2021/7/22
N2 - 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 vitroandin vivostudies 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.
AB - 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 vitroandin vivostudies 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.
UR - http://www.scopus.com/inward/record.url?scp=85110958457&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00437
DO - 10.1021/acs.jmedchem.1c00437
M3 - Article
C2 - 34191513
AN - SCOPUS:85110958457
SN - 0022-2623
VL - 64
SP - 10155
EP - 10166
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -