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
2020
Online
academicJournal
Zugriff:
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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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
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Autor/in / Beteiligte Person: | Davies, David T. ; Leiris, Simon ; Zalacain, Magdalena ; Sprynski, Nicolas ; Castandet, Jérôme ; Bousquet, Justine ; Lozano, Clarisse ; Llanos, Agustina ; Alibaud, Laethitia ; Vasa, Srinivas ; Pattipati, Ramesh ; Valige, Ravindar ; Kummari, Bhaskar ; Pothukanuri, Srinivasu ; De Piano, Cyntia ; Morrissey, Ian ; Holden, Kirsty ; Warn, Peter ; Marcoccia, Francesca ; Benvenuti, Manuela ; Pozzi, Cecilia ; Tassone, Giusy ; Mangani, Stefano ; Docquier, Jean-Denis ; Pallin, David ; Elliot, Richard ; Lemonnier, Marc ; Everett, Martin |
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Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
DOI: | 10.1021/acs.jmedchem.0c01535 |
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