4.5 Article

Mechanistic Investigations of Metallo-β-lactamase Inhibitors: Strong Zinc Binding Is Not Required for Potent Enzyme Inhibition**

期刊

CHEMMEDCHEM
卷 16, 期 10, 页码 1651-1659

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100042

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antibiotic resistance; MBL inhibitors; metallo-beta-lactamases; synergy; zinc binding

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This study elucidated the inhibitory mechanisms of a panel of structurally distinct MBL inhibitors, finding clear differences in terms of IC50 value, metal binding ability, and synergy with meropenem. The capacity of an inhibitor to strongly chelate zinc does not explicitly determine potent MBL inhibition and synergy with meropenem.
Metallo-beta-lactamases (MBLs) are zinc-dependent bacterial enzymes that inactivate essentially all classes of beta-lactam antibiotics including last-resort carbapenems. At present there are no clinically approved MBL inhibitors, and in order to develop such agents it is essential to understand their inhibitory mechanisms. Herein, we describe a comprehensive mechanistic study of a panel of structurally distinct MBL inhibitors reported in both the scientific and patent literature. Specifically, we determined the half-maximal inhibitory concentration (IC50) for each inhibitor against MBLs belonging to the NDM and IMP families. In addition, the binding affinities of the inhibitors for Zn2+, Ca2+ and Mg(2+ )were assessed by using isothermal titration calorimetry (ITC). We also compared the ability of the different inhibitors to resensitize a highly resistant MBL-expressing Escherichia coli strain to meropenem. These investigations reveal clear differences between the MBL inhibitors studied in terms of their IC50 value, metal binding ability, and capacity to synergize with meropenem. Notably, our studies demonstrate that potent MBL inhibition and synergy with meropenem are not explicitly dependent on the capacity of an inhibitor to strongly chelate zinc.

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