Nature Microbiology 2017-06-30

ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii

Thomas F. Durand-Réville, Satenig Guler, Janelle Comita-Prevoir, Brendan Chen, Neil Bifulco, Hoan Huynh, Sushmita Lahiri, Adam B. Shapiro, Sarah M. McLeod, Nicole M. Carter, Samir H. Moussa, Camilo Velez-Vega, Nelson B. Olivier, Robert McLaughlin, Ning Gao, Jason Thresher, Tiffany Palmer, Beth Andrews, Robert A. Giacobbe, Joseph V. Newman, David E. Ehmann, Boudewijn de Jonge, John O'Donnell, John P. Mueller, Rubén A. Tommasi, Alita A. Miller

Index: 10.1038/nmicrobiol.2017.104

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Abstract

Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of β-lactamases, enzymes that inactivate β-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new β-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine β-lactamase inhibitors that potently inhibit clinically relevant class A, C and D β-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of β-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam–ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.