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
  • 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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