Mechanistic Investigations of Metallo‐β‐lactamase Inhibitors: Strong Zinc Binding Is Not Required for Potent Enzyme Inhibition. (3rd March 2021)

• Record Type: Journal Article
• Authors: Wade, Nicola; Tehrani, Kamaleddin H. M. E.; Brüchle, Nora C.; van Haren, Matthijs J.; Mashayekhi, Vida; Martin, Nathaniel I.
• Is Part Of: ChemMedChem. Volume 16:Number 10(2021)
• Page Start: 1651
• Page End: 1659
• Publication Date: 2021-03-03
• Subjects: antibiotic resistance -- MBL inhibitors -- metallo-beta-lactamases -- synergy -- zinc binding; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100042
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Metallo‐β‐lactamases (MBLs) are zinc‐dependent bacterial enzymes that inactivate essentially all classes of β‐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 Zn 2+, Ca 2+ 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. Abstract : Developing broad‐spectrum MBL inhibitors : Structurally diverse MBL inhibitors were assessed for their ability to inhibit purified MBL enzymes, bind various divalent cations, and resensitize a carbapenem‐resistant E. coli strain to meropenem. These studies reveal that potent MBL inhibition and synergy with meropenem is not explicitly dependent on the ability of an inhibitor to bind free zinc with high affinity.