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SAR studies leading to the identification of a novel series of metallo-β-lactamase inhibitors for the treatment of carbapenem-resistant Enterobacteriaceae infections that display efficacy in an animal infection model

DOI: 10.1021/acsinfecdis.8b00246 DOI Help

Authors: Simon Leiris (Antabio SAS) , Alicia Coelho (Antabio SAS) , Jérôme Castandet (Antabio SAS) , Maëlle Bayet (Antabio SAS) , Clarisse Lozano (Antabio SAS) , Juliette Bougnon (Antabio SAS) , Justine Bousquet (Antabio SAS) , Martin John Everett (Antabio SAS) , Marc Lemonnier (Antabio SAS) , Nicolas Sprynski (Antabio SAS) , Magdalena Zalacain (Antabio SAS; Zala Drug Discovery Consulting LLC) , Thomas David Pallin (Charles River Laboratories) , Michael Cramp (Charles River Laboratories) , Neil Jennings (Charles River Laboratories) , Gilles Raphy (Charles River Laboratories) , Mark William Jones (Charles River Laboratories) , Ramesh Pattipati (GVK Biosciences Private Limited) , Battu Shankar (GVK Biosciences Private Limited) , Relangi Sivasubrahmanyam (GVK Biosciences Private Limited) , Ashok Kumar Soodhagani (GVK Biosciences Private Limited) , Ramakrishna Reddy Juventhala (GVK Biosciences Private Limited) , Narender Pottabathini (GVK Biosciences Private Limited) , Srinivasu Pothukanuri (GVK Biosciences Private Limited) , Manuela Benvenuti (University of Siena) , Cecilia Pozzi (University of Siena) , Stefano Mangani (University of Siena) , Filomena De Luca (University of Siena) , Giulia Cerboni (University of Siena) , Jean-denis Docquier (University of Siena) , David Davies (Antabio SAS)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 8574 , 15832

Abstract: The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo β-lactamase (MBL) and serine β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein we describe our initial exploration of a novel chemical series of metallo β-lactamase inhibitors, from concept through to efficacy in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.

Journal Keywords: antibiotic resistance; metallo β-lactamase inhibitor; NDM-1; VIM-2; meropenem; efficacy

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

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