Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Trout RE

PROVIDER: S-EPMC8311649 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Trout Robert E RE Zulli Allison A Mesaros Eugen E Jackson Randy W RW Boyd Steven S Liu Bin B Hamrick Jodie J Daigle Denis D Chatwin Cassandra L CL John Kaitlyn K McLaughlin Lisa L Cusick Susan M SM Weiss William J WJ Pulse Mark E ME Pevear Daniel C DC Moeck Greg G Xerri Luigi L Burns Christopher J CJ

Journal of medicinal chemistry 20210630 14

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 m ...[more]

PMID: 34191513

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Project description:ObjectivesThis study assessed the activity of ceftibuten, ceftibuten combined with the active form (VNRX-5236) of the β-lactamase inhibitor VNRX-7145 and comparators against a challenge set of Gram-negative pathogens.MethodsTwo hundred and five Enterobacterales carrying plasmid AmpC (53 isolates), ESBL (50), KPC (50), OXA-48-like (49) or OXA-48-like with KPC (3) encoding genes were selected. Susceptibility was determined by broth microdilution. VNRX-5236 and avibactam were tested at a fixed concentration of 4 mg/L.ResultsCeftibuten/VNRX-5236 (MIC50/90 0.12/1 mg/L) MIC values were 256-fold lower than those of ceftibuten (MIC50/90 32/256 mg/L) for all Enterobacterales and 2- to 4-fold lower than those of ceftazidime/avibactam (MIC50/90 0.5/2 mg/L). For isolates producing a plasmid-encoded AmpC, VNRX-5236 decreased ceftibuten MIC (MIC50/90 0.12/1 mg/L) by at least 512-fold compared with ceftibuten (MIC50/90 128/>256 mg/L). Ceftibuten/VNRX-5236 (MIC50/90 0.06/0.12 mg/L) and meropenem (MIC50/90 ≤0.03/0.06 mg/L; 100% susceptible) showed comparable activities against ESBL isolates and these agents had MIC90 values 4- to 8-fold lower than that of ceftazidime/avibactam (MIC50/90 0.25/0.5 mg/L; 100% susceptible). Ceftibuten/VNRX-5236 (MIC50/90 0.12/0.5 mg/L) had the lowest MIC for KPC producers, followed by ceftazidime/avibactam (MIC50/90 2/4 mg/L; 98.0% susceptible). The same MIC90 values were obtained for ceftibuten/VNRX-5236 (MIC50/90 0.25/1 mg/L) and ceftazidime/avibactam (MIC50/90 1/1 mg/L; 100.0% susceptible) for isolates carrying blaOXA-48-like. VNRX-5236 decreased the ceftibuten MIC at least 16-fold for three isolates carrying blaOXA-48-like and blaKPC.ConclusionsVNRX-5236 rescued the in vitro activity of ceftibuten against Enterobacterales carrying common serine β-lactamases, including ESBL, AmpC and the KPC and OXA-48-like carbapenemases. Ceftibuten/VNRX-5236 may have potential as an oral treatment for infections caused by resistant Enterobacterales, while sparing carbapenems.

Project description:Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

Dataset Information

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

Publications

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

Similar Datasets

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