Structural and sequence analysis of class A β-lactamases with respect to avibactam inhibition: impact of Ω-loop variations.
Background: There exists a significant diversity among class A β-lactamases and the proliferation of these enzymes is a significant medical concern due to the ability of some members to efficiently hydrolyse both extended-spectrum cephalosporins and carbapenems. Avibactam is a novel non-β-lactam β-l...
| Publicado en: | Journal of Antimicrobial Chemotherapy (JAC) Vol. 71; no. 10; pp. 2848 - 2856 |
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| Autores principales: | , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Oxford University Press / USA
Oct2016
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=118300510&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 118300510 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03057453 N5O jtl: Journal of Antimicrobial Chemotherapy (JAC) issn: 03057453 maglogo: N pubinfo: dt: Oct2016 vid: 71 iid: 10 pid: 622 pub: Oxford University Press / USA artinfo: ui: 118300510 118300510 NLM27402011 118300510 10.1093/jac/dkw248 NLM27402011 118300510 ppf: 2848 ppct: 8 formats: tig: atl: Structural and sequence analysis of class A β-lactamases with respect to avibactam inhibition: impact of Ω-loop variations. aug: au: Lahiri, Sushmita D. Bradford, Patricia A. Nichols, Wright W. Alm, Richard A. affil: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA, USA sug: subj: Hydrolases Klebsiella Enzyme Inhibitors Pharmacodynamics Hydrolases Metabolism Escherichia Coli Antibiotics Pharmacodynamics Organic Chemicals Pharmacodynamics Bacterial Proteins Ceftazidime Pharmacodynamics Molecular Structure Microbial Culture and Sensitivity Tests Models, Theoretical Organic Chemicals Metabolism Bacterial Proteins Metabolism Klebsiella Drug Effects Enzyme Inhibitors Metabolism Escherichia Coli Drug Effects Hydrolases Classification Binding Sites Sequence Analysis ab: Background: There exists a significant diversity among class A β-lactamases and the proliferation of these enzymes is a significant medical concern due to the ability of some members to efficiently hydrolyse both extended-spectrum cephalosporins and carbapenems. Avibactam is a novel non-β-lactam β-lactamase inhibitor that, in combination with ceftazidime, has recently obtained regulatory approval in the USA. Although avibactam is known to efficiently inhibit key class A enzymes, the diversity of this enzyme family warranted a more complete investigation to understand the breadth of the potential spectrum of inhibition.Methods: Using the known residues critical for avibactam binding, a thorough structural and sequence-based conservation analysis was performed across >650 class A enzymes. Several variations that had the potential to impact avibactam inhibition were observed and representative enzymes were cloned and expressed isogenically to evaluate the impact of these variations.Results: The majority of the key residues involved in avibactam binding were well conserved across the different sub-families of class A β-lactamases, although some differences were observed. The differences in the Ω-loop of PER enzymes were found to impact the ability of avibactam to effectively protect β-lactams against hydrolysis. However, substitutions in a key hydrogen-bonding residue (N170) in some of the GES variants were found to not have a significant impact on avibactam inhibition.Conclusions: Overall, the computational and experimental analyses suggest that the vast majority of class A β-lactamases should be well inhibited by avibactam, although a very small number of outliers exist. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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