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Discovery of ant3310, a novel broad-spectrum serine β-lactamase inhibitor of the diazabicyclooctane class, which strongly potentiates meropenem activity against carbapenem-resistant enterobacterales and Acinetobacter baumannii

DOI: 10.1021/acs.jmedchem.0c01535 DOI Help

Authors: David T. Davies (Antabio SAS) , Simon Leiris (Antabio SAS) , Magdalena Zalacain (Antabio SAS) , Nicolas Sprynski (Antabio SAS) , Jérôme Castandet (Antabio SAS) , Justine Bousquet (Antabio SAS) , Clarisse Lozano (Antabio SAS) , Agustina Llanos (Antabio SAS) , Laethitia Alibaud (Antabio SAS) , Srinivas Vasa (GVK Biosciences Pvt. Ltd) , Ramesh Pattipati (GVK Biosciences Pvt. Ltd) , Ravindar Valige (GVK Biosciences Pvt. Ltd) , Bhaskar Kummari (GVK Biosciences Pvt. Ltd) , Srinivasu Pothukanuri (GVK Biosciences Pvt. Ltd) , Cyntia De Piano (International Health Management Associates (IHMA)) , Ian Morrissey (International Health Management Associates (IHMA)) , Kirsty Holden (Evotec (UK) Ltd) , Peter Warn (Evotec (UK) Ltd) , Francesca Marcoccia (University of Siena) , Manuela Benvenuti (University of Siena) , Cecilia Pozzi (University of Siena) , Giusy Tassone (University of Siena) , Stefano Mangani (University of Siena) , Jean-Denis Docquier (University of Siena) , David Pallin (Charles River Laboratories) , Richard Elliot (Charles River Laboratories) , Marc Lemonnier (Antabio SAS) , Martin Everett (Antabio SAS)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2020
Diamond Proposal Number(s): 21741

Abstract: The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO “critical priority pathogen” producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure–activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)