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 .

Autor: Davies DT; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Leiris S; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Zalacain M; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Sprynski N; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Castandet J; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Bousquet J; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Lozano C; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Llanos A; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Alibaud L; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Vasa S; GVK Biosciences Pvt. Ltd., Survey No. 125 and 126, IDA, Mallapur, Hyderabad, Telangana 500 076, India., Pattipati R; GVK Biosciences Pvt. Ltd., Survey No. 125 and 126, IDA, Mallapur, Hyderabad, Telangana 500 076, India., Valige R; GVK Biosciences Pvt. Ltd., Survey No. 125 and 126, IDA, Mallapur, Hyderabad, Telangana 500 076, India., Kummari B; GVK Biosciences Pvt. Ltd., Survey No. 125 and 126, IDA, Mallapur, Hyderabad, Telangana 500 076, India., Pothukanuri S; GVK Biosciences Pvt. Ltd., Survey No. 125 and 126, IDA, Mallapur, Hyderabad, Telangana 500 076, India., De Piano C; International Health Management Associates (IHMA), Rte. De I'Ile-au-Bois 1A, 1870 Monthey, Switzerland., Morrissey I; International Health Management Associates (IHMA), Rte. De I'Ile-au-Bois 1A, 1870 Monthey, Switzerland., Holden K; Evotec (UK) Ltd., Block 23, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K., Warn P; Evotec (UK) Ltd., Block 23, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K., Marcoccia F; Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, Siena 53100, Italy., Benvenuti M; Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, Siena 53100, Italy., Pozzi C; Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, Siena 53100, Italy., Tassone G; Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, Siena 53100, Italy., Mangani S; Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Via Aldo Moro 2, Siena 53100, Italy., Docquier JD; Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, Siena 53100, Italy., Pallin D; Charles River Laboratories, 8-9 The Spire Green Centre, Harlow, Essex CM19 5TR, U.K., Elliot R; Charles River Laboratories, 8-9 The Spire Green Centre, Harlow, Essex CM19 5TR, U.K., Lemonnier M; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France., Everett M; Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 Dec 24; Vol. 63 (24), pp. 15802-15820. Date of Electronic Publication: 2020 Dec 11.
DOI: 10.1021/acs.jmedchem.0c01535
Abstrakt: 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.
Databáze: MEDLINE
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