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

  • J Med Chem. 2020 Nov 12;63(21):12511-12525. doi: 10.1021/acs.jmedchem.0c00579.
Thomas F Durand-Réville  1 ,  Janelle Comita-Prevoir  1 ,  Jing Zhang  1 ,  Xiaoyun Wu  1 ,  Tricia L May-Dracka  2 ,  Jan Antoinette C Romero  1 ,  Frank Wu  1 ,  April Chen  1 ,  Adam B Shapiro  1 ,  Nicole M Carter  1 ,  Sarah M McLeod  1 ,  Robert A Giacobbe  2 ,  Jeroen C Verheijen  2 ,  Sushmita D Lahiri  2 ,  Michael D Sacco  3 ,  Yu Chen  3 ,  John P O'Donnell  1 ,  Alita A Miller  1 ,  John P Mueller  1 ,  Rubén A Tommasi  1
Affiliations
  • 1. Entasis Therapeutics, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 2. Infection Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 3. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
PMID: 32658473 DOI: 10.1021/acs.jmedchem.0c00579
Abstract

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.

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