Dataset Information

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C ?-Lactamase from Escherichia coli.

ABSTRACT: Resistance to ?-lactam antibacterials, importantly via production of ?-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) ?-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 ??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 ?-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D ??lactamases, our data support the proposal that bicyclic boronates are broad-spectrum ??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 ?-lactamase inhibition.

SUBMITTER: Lang PA

PROVIDER: S-EPMC7356297 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from <i>Escherichia coli</i>.

Lang Pauline A PA Parkova Anete A Leissing Thomas M TM Calvopiña Karina K Cain Ricky R Krajnc Alen A Panduwawala Tharindi D TD Philippe Jules J Fishwick Colin W G CWG Trapencieris Peteris P Page Malcolm G P MGP Schofield Christopher J CJ Brem Jürgen J

Biomolecules 20200612 6

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 ...[more]

PMID: 32545682

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Project description:A nationwide study on the occurrence of extended-spectrum β-lactamase (ESBL)/AmpC in nonhospitalized horses in the Netherlands was performed. Molecular characterization was done, and questionnaires were analyzed to identify factors associated with carriage. In total, 796 horse owners were approached; 281 of these submitted a fecal sample from their horse(s), resulting in 362 samples. All samples were cultured qualitatively in Luria-Bertani (LB) broth and subsequently on MacConkey agar, both supplemented with 1 mg/liter cefotaxime (LB+ and MC+). Positive samples were subsequently cultured quantitatively on MC+. Initial extended-spectrum-β-lactamase (ESBL)/AmpC screening was performed by PCR, followed by whole-genome sequencing on selected strains. Associations between ESBL/AmpC carriage and questionnaire items were analyzed using a univariate generalized estimating equation (GEE) regression analysis, followed by a multiple GEE model for relevant factors. In total, 39 of 362 samples (11%) were determined to be positive for ESBL/AmpC. blaCTX-M-1-carrying isolates were obtained from 77% of positive samples (n = 30). Other ESBL/AmpC genes observed included blaCTX-M-2, blaCTX-M-14, blaCTX-M-15, blaCTX-M-32, blaSHV-12, blaCMY-2, and blaACT-10 A high association between the presence of blaCTX-M-1 and IncHI1 plasmids was observed (46% of samples; n = 18). Based on core genome analysis (n = 48 isolates), six Escherichia coli clusters were identified, three of which represented 80% of the isolates. A negative association between ESBL/AmpC carriage and horses being in contact with other horses at a different site was observed. The presence of a dog on the premises and housing in a more densely human-populated region were positively associated.IMPORTANCE Extended-spectrum β-lactamases (ESBLs) are widespread in human and animal populations and in the environment. Many different ESBL variants exist. The dissemination of ESBLs within and between populations and the environment is also largely influenced by genetic mobile elements (e.g., plasmids) that facilitate spread of these ESBLs. In order to identify potential attributable ESBL sources for, e.g., the human population, it is important to identify the different ESBL variants, the bacteria carrying them, and the potential risk factors for ESBL carriage from other potential sources. This nationwide study focuses on ESBL carriage in the open horse population and investigated the molecular characteristics, geographical distribution throughout the Netherlands, and potential risk factors for fecal ESBL carriage in horses. These data can be used for future attribution studies in order to reduce potential transmission of ESBL-producing bacteria between sources.

Dataset Information

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C ?-Lactamase from Escherichia coli.

Publications

Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from <i>Escherichia coli</i>.

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