2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Dec 24;63(24):15802-15820. doi: 10.1021/acs.jmedchem.0c01535.
David T Davies 1,  Simon Leiris 1,  Magdalena Zalacain 1,  Nicolas Sprynski 1,  Jérôme Castandet 1,  Justine Bousquet 1,  Clarisse Lozano 1,  Agustina Llanos 1,  Laethitia Alibaud 1,  Srinivas Vasa 2,  Ramesh Pattipati 2,  Ravindar Valige 2,  Bhaskar Kummari 2,  Srinivasu Pothukanuri 2,  Cyntia De Piano 3,  Ian Morrissey 3,  Kirsty Holden 4,  Peter Warn 4,  Francesca Marcoccia 5,  Manuela Benvenuti 6,  Cecilia Pozzi 6,  Giusy Tassone 6,  Stefano Mangani 6,  Jean-Denis Docquier 5,  David Pallin 7,  Richard Elliot 7,  Marc Lemonnier 1,  Martin Everett 1
Affiliations

Affiliations

  • 1 Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France.
  • 2 GVK Biosciences Pvt. Ltd., Survey No. 125 and 126, IDA, Mallapur, Hyderabad, Telangana 500 076, India.
  • 3 International Health Management Associates (IHMA), Rte. De I'Ile-au-Bois 1A, 1870 Monthey, Switzerland.
  • 4 Evotec (UK) Ltd., Block 23, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
  • 5 Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, Siena 53100, Italy.
  • 6 Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, Siena 53100, Italy.
  • 7 Charles River Laboratories, 8-9 The Spire Green Centre, Harlow, Essex CM19 5TR, U.K.
PMID: 33306385 DOI: 10.1021/acs.jmedchem.0c01535
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.

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