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

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

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.

Figures
Products