Journal
BIOMOLECULES
Volume 10, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/biom10060899
Keywords
antibiotic resistance; beta-lactam antibacterial; bicyclic boronate inhibitors; VNRX-5133; taniborbactam; vaborbactam; metallo; and serine-beta-lactamase inhibition; transition state analogue
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Funding
- National PhD Training Programme in Antimicrobial Resistance Research by the Medical Research Foundation [MRF-145-0004-TPG-AVISO]
- Wellcome Trust
- Medical Research Council
- Biotechnology and Biological Research Council [BB/S50676X/1]
- Innovative Medicines Initiative (European Lead factory)
- Innovative Medicines Initiative (ENABLE components)
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Resistance to beta-lactam antibacterials, importantly via production of beta-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) beta-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 beta-lactamase fromEscherichia 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 beta-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D beta-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum beta-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 beta-lactamase inhibition.
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