Abstract
Bacterial resistance represents a worldwide emergency threatening the efficacy of all available antibiotics. Among the several resistance mechanisms developed by bacteria, β-lactamase enzymes (BLs), which are able to inactivate most β-lactam core antibiotics, represent a key target to block, thus prolonging antibiotics half-life. Several approaches aimed at inhibiting β-lactamases have been so far undertaken, mainly involving β-lactam-like or covalent inhibitors. Applying a structure-based de novo design approach, we recently discovered a novel, non-covalent and competitive inhibitor of AmpC β-lactamase: lead 1. It has a K i of 1 µM, a ligand efficiency of 0.38 kcal mol−1 and lead-like physical properties. Moreover, it reverts resistance to ceftazidime in bacterial pathogens expressing AmpC and does not up-regulate β-lactamases expression in cell culture. Its features make it a good candidate for chemical optimization: starting from lead 1 crystallographic complex with AmpC, 11 analogs were designed to complement additional AmpC sites, then synthesized and tested against clinically resistant pathogens. While the new inhibitors maintain similar in vitro activity as the starting lead, some of them, in biological assays, extert a higher potency showing improved synergic activity with ceftazidime in resistant clinically isolated strains.
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Acknowledgements
This work was supported by NIH GM63815, by FAR 2014, University of Modena to DT, by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III, the Spanish Network for Research in Infectious Diseases RD12/0015/0029 and Fondo de Investigación Sanitaria Grant PI13/00063. C.I-Q. was supported by a grant from “Becas para estudios de doctorado en el extranjero” from Chile Scholarship Program (72110933), National Council for Scientific and Technological Research (CONICYT), Chilean Government. The authors acknowledge the “Fondazione Cassa di Risparmio di Modena” for funding the HPLC-ESI-QTOF system at the Centro Interdipartimentale Grandi Strumenti of the University of Modena and Reggio Emilia. We acknowledge Dr. Pasquale Linciano for support in NMR compounds characterization.
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Genovese, F., Lazzari, S., Venturi, E. et al. Design, synthesis and biological evaluation of non-covalent AmpC β-lactamases inhibitors. Med Chem Res 26, 975–986 (2017). https://doi.org/10.1007/s00044-017-1809-x
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DOI: https://doi.org/10.1007/s00044-017-1809-x