Design, synthesis and biological evaluation of non-covalent AmpC beta-lactamases inhibitors

作者：Genovese Filippo; Lazzari Sandra; Venturi Ettore; Costantino Luca; Blazquez Jesus; Ibacache Quiroga Claudia; Costi Maria Paola; Tondi Donatella^*

来源：Medicinal Chemistry Research, 2017, 26(5): 975-986.

DOI：10.1007/s00044-017-1809-x

• Structure-based de novo design
• Thiophene derivatives
• Non covalent beta-lactamases inhibitor
• Synthesis
• Minimum inhibitory concentration (MIC)

Bacterial resistance represents a worldwide emergency threatening the efficacy of all available antibiotics. Among the several resistance mechanisms developed by bacteria, beta-lactamase enzymes (BLs), which are able to inactivate most beta-lactam core antibiotics, represent a key target to block, thus prolonging antibiotics half-life. Several approaches aimed at inhibiting beta-lactamases have been so far undertaken, mainly involving beta-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 beta-lactamase: lead 1. It has a K-i of 1 mu M, 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 beta-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.

• 出版日期2017-5