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 <i>Enterobacteriaceae</i>
David T. Davies, Simon Leiris, Nicolas Sprynski, Jérôme Castandet, Clarisse Lozano, Justine Bousquet, Magdalena Zalacaín, Srinivas Vasa, Praveen K. Dasari, Ramesh Pattipati, Naresh Vempala, Swetha Gujjewar, SyamKumar Godi, Raju Jallala, Rajashekar Reddy Sathyap, Narasimha A. Darshanoju, Vengala R. Ravu, Ramakrishna R. Juventhala, Narender Pottabathini, Somesh Sharma, Srinivasu Pothukanuri, Kirsty Holden, Peter Warn, Francesca Marcoccia, Manuela Benvenuti, Cecilia Pozzi, Stefano Mangani, Jean‐Denis Docquier, Marc Lemonnier, Martin Everett
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.