Advancements in the fight against globally distributed OXA-48 carbapenemase: evaluating the new generation of carbapenemase inhibitors
Michelle Outeda-García, Jorge Arca-Suárez, Emilio Lence, Arianna Rodríguez-Coello, Romina Maceiras, Tania Blanco-Martín, Paula Guijarro-Sánchez, Lucía González-Pinto, Isaac Alonso-García, Andrea García-Pose, Andrea Muras, Salud Rodríguez-Pallares, Cristina Lasarte-Monterrubio, Concepción González‐Bello, Juan Carlos Vázquez-Ucha, Germán Bou, Alejandro Beceiro
Abstract
, the infections they cause are challenging to treat with conventional therapies, owing to their spread and complex detection in clinical settings. However, numerous β-lactamase inhibitors (BLIs) are currently in the pipeline or late clinical stages. To assess the potential of these compounds, this study compared the efficacy against OXA-48 of novel β-lactamase inhibitors, specifically the 1,6-diazabicyclo[3,2,1]octanes (DBOs) avibactam, relebactam, zidebactam, nacubactam, and durlobactam, along with the cyclic and bicyclic boronates vaborbactam, taniborbactam, and xeruborbactam. The extensive kinetics assays identified xeruborbactam, taniborbactam, and durlobactam, together with the already established avibactam, as BLIs with superior biochemical performance. Susceptibility testing further validated these findings but also demonstrated significantly improved bacterial killing by the DBOs zidebactam, nacubactam, and durlobactam. On the other hand, binding studies demonstrated the superior inhibitory capacity of the BLIs durlobactam and xeruborbactam. Combinations, such as cefepime/zidebactam, meropenem/nacubactam, and sulbactam/durlobactam, show promising activity against OXA-48-producing Enterobacterales, while ceftazidime/avibactam, cefepime/taniborbactam, and meropenem/xeruborbactam combinations also appear highly active, largely due to the excellent kinetics of these new inhibitors. Overall, this comprehensive analysis provides important insights into the effectiveness of new BLIs against OXA-48-producing Enterobacterales, highlighting xeruborbactam, durlobactam, and avibactam as leading candidates. Additionally, BLIs like zidebactam, nacubactam, and taniborbactam also showed potential in addressing the clinical challenges posed by OXA-48-mediated antimicrobial resistance.