ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens <i>In Vivo</i>
Ørjan Samuelsen, Ove Alexander Høgmoen Åstrand, Christopher Fröhlich, Adam Heikal, Susann Skagseth, Trine Josefine Olsen Carlsen, Hanna‐Kirsti S. Leiros, Annette Bayer, Christian Schnaars, Geir Kildahl‐Andersen, Silje Lauksund, Sarah Finke, Sandra Huber, Tor Gjøen, Adriana Magalhães Santos Andresen, Ole Andreas Økstad, Pål Rongved
Abstract
mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.