Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli
Open Access
- 12 June 2020
- journal article
- research article
- Published by MDPI AG in Biomolecules
- Vol. 10 (6), 899
- https://doi.org/10.3390/biom10060899
Abstract
Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition.Keywords
Funding Information
- Medical Research Foundation (MRF-145-0004-TPG-AVISO)
- Biotechnology and Biological Sciences Research Council (BB/S50676X/1)
- Innovative Medicines Initiative (European Lead factory and ENABLE components)
This publication has 51 references indexed in Scilit:
- Assay Platform for Clinically Relevant Metallo-β-lactamasesJournal of Medicinal Chemistry, 2013
- Features and development of CootActa crystallographica. Section D, Structural biology, 2010
- Updated Functional Classification of β-LactamasesAntimicrobial Agents and Chemotherapy, 2010
- Three Decades of β-Lactamase InhibitorsClinical Microbiology Reviews, 2010
- Observations on the Deprotection of Pinanediol and Pinacol Boronate Esters via Fluorinated IntermediatesThe Journal of Organic Chemistry, 2009
- AmpC β-LactamasesClinical Microbiology Reviews, 2009
- Phasercrystallographic softwareJournal of Applied Crystallography, 2007
- Structures of Ceftazidime and Its Transition-State Analogue in Complex with AmpC β-Lactamase: Implications for Resistance Mutations and Inhibitor Design,Biochemistry, 2001
- The E. coli β-lactamase attenuator mediates growth rate-dependent regulationNature, 1981
- Augmentin (amoxycillin and clavulanic acid) therapy in complicated infections due to ?-lactamase producing bacteriaJournal of Antimicrobial Chemotherapy, 1981