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ANT2681: SAR studies leading to the identification of a metallo-β-lactamase inhibitor with potential for clinical use in combination with meropenem for the treatment of infections caused by NDM-producing Enterobacteriaceae

DOI: 10.1021/acsinfecdis.0c00207 DOI Help

Authors: David T. Davies (Antabio SAS) , Simon Leiris (Antabio SAS) , Nicolas Sprynski (Antabio SAS) , Jérôme Castandet (Antabio SAS) , Clarisse Lozano (Antabio SAS) , Justine Bousquet (Antabio SAS) , Magdalena Zalacain (Antabio SAS) , Srinivas Vasa (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Praveen K. Dasari (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Ramesh Pattipati (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Naresh Vempala (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Swetha Gujjewar (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Syamkumar Godi (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Raju Jallala (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Rajashekar Reddy Sathyap (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Narasimha A. Darshanoju (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Vengala R. Ravu (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Ramakrishna R. Juventhala (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Narender Pottabathini (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Somesh Sharma (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Srinivasu Pothukanuri (Srinivas Vasa - GVK Biosciences Pvt. Ltd) , Kirsty Holden (Evotec (U.K.) Ltd) , Peter Warn (Evotec (U.K.) Ltd) , Francesca Marcoccia (University of Siena) , Manuela Benvenuti (University of Siena) , Cecilia Pozzi (University of Siena) , Stefano Mangani (University of Siena) , Jean-denis Docquier (University of Siena) , Marc Lemonnier (Antabio SAS) , Martin Everett (AntabioSAS)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 21741

Abstract: The clinical effectiveness of the important β-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-β-lactamase (MBL) enzymes. To address this resistance issue, multiple β-lactam/β-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.

Journal Keywords: metallo-β-lactamase inhibitor; New Delhi metallo-β-lactamase (NDM); antibiotic resistance; meropenem; carbapenem-resistant Enterobacteriaceae; ANT2681

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-Macromolecular Crystallography

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