Targeting clinically-relevant metallo-β-lactamases: from high-throughput docking to broad-spectrum inhibitors

Abstract

Metallo-β-lactamases (MBLs) represent one of the most important and widespread mechanisms of resistance to β-lactam antibiotics (including the life-saving carbapenems), against which no clinically useful inhibitors are currently available. We report herein a structure-based high-throughput docking (HTD) campaign on three clinically-relevant acquired MBLs (IMP-1, NDM-1 and VIM-2). The initial hit NF1810 (1) was optimized providing the broad-spectrum inhibitor 3i, which is able to potentiate the in vitro activity of cefoxitin on a VIM-2-producing E. coli strain.

Keywords:

• Antibiotic resistance
• docking
• metallo-β-lactamase

Acknowledgements

The authors wish to thank Prof. Nielsen (University of Copenhagen, Denmark) and Dr. Good (Royal Veterinary College, London, U.K.) for kindly providing the E. coli AS19 strain.

Declaration of interest

Part of this work was supported by the Italian Foundation for Cystic Fibrosis Research with the contribution of Antonio Guadagni&Figli, Delegazione FFC Manciano Grosseto e famiglia Catalano, Hotel Metropole (grants FFC#16/2015 to S.G. and J.-D.D.). The authors report no declarations of interest.