Acquired Class D β-Lactamases

Antunes, Nuno T.; Fisher, Jed F.

doi:10.3390/antibiotics3030398

Cited by 71 publications

(73 citation statements)

References 180 publications

(288 reference statements)

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“…OXA-48 family member identification, including OXA-48, OXA-54, OXA-162, OXA-163, OXA-181, OXA-199, OXA-204, OXA-232, OXA-244, OXA-245, OXA-247, and OXA-370, consistent with other reported family classifications for the OXA-48 ␤-lactamase (Table S4) (3,9).…”

supporting

confidence: 88%

Identification of the OXA-48 Carbapenemase Family by Use of Tryptic Peptides and Liquid Chromatography-Tandem Mass Spectrometry

et al. 2019

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Phenotypic detection of the OXA-48-type class D ␤-lactamases in Enterobacteriaceae is challenging. We describe a rapid (less than 90 min) assay for the identification of OXA-48 family carbapenemases in subcultured bacterial isolates based on a genoproteomic approach. Following in silico trypsin digestion to ascertain theoretical core peptides common to the OXA-48 family, liquid chromatography-tandem mass spectrometry (LC-MS/MS) data-dependent acquisition was used to identify candidate peptide markers. Two peptides were selected based on performance characteristics: ANQAFLPASTFK, a core peptide common to all 12 OXA-48 family ␤-lactamase members, and YSVVPVYQEFAR, a highly specific peptide common to 11 of 12 OXA-48 family proteins providing the basis for an LC-MS/MS multiple reaction monitoring assay. An accuracy assessment was performed that included 98 isolates, 26 of which were OXA-48 positive. Two additional specificity assessments were performed including a mixture of isolates positive for OXA-48, KPC, NDM, VIM, and IMP carbapenemases. A combination of expert rules and expert judgment was applied by blinded operators to identify positive isolates. All isolates containing an OXA-48 family carbapenemase across all three test sets were correctly identified with no false positives, demonstrating 100% sensitivity (95% confidence interval [CI], 91.2% to 100%) and 100% specificity (95% CI, 96.2% to 100%) for the assay. These findings provide a framework for an LC-MS/MS-based method for the direct detection of OXA-48 family carbapenemases from cultured isolates that may have utility in predicting carbapenem resistance and tracking hospital outbreaks of OXA-48-carrying organisms.

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supporting

confidence: 88%

Identification of the OXA-48 Carbapenemase Family by Use of Tryptic Peptides and Liquid Chromatography-Tandem Mass Spectrometry

et al. 2019

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“…Class D ␤-lactamases are also known as oxacillinases (OXA ␤-lactamases) due to their ability to hydrolyze the oxacillin subclass of the penicillins (3). The OXA ␤-lactamases were first observed to be a resistance mechanism against imipenem in the mid-1980s, coincidentally in the same year imipenem was introduced for clinical use (4,5).…”

mentioning

confidence: 99%

Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

Pratap

Katiki

Gill

et al. 2016

Antimicrob Agents Chemother

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Carbapenem-hydrolyzing class D ␤-lactamases (CHDLs) are a subgroup of class D ␤-lactamases, which are enzymes that hydrolyze ␤-lactams. They have attracted interest due to the emergence of multidrug-resistant Acinetobacter baumannii, which is not responsive to treatment with carbapenems, the usual antibiotics of choice for this bacterium. Unlike other class D ␤-lactamases, these enzymes efficiently hydrolyze carbapenem antibiotics. To explore the structural requirements for the catalysis of carbapenems by these enzymes, we determined the crystal structure of the OXA-58 CHDL of A. baumannii following acylation of its active-site serine by a 6␣-hydroxymethyl penicillin derivative that is a structural mimetic for a carbapenem. In addition, several point mutation variants of the active site of OXA-58, as identified by the crystal structure analysis, were characterized kinetically. These combined studies confirm the mechanistic relevance of a hydrophobic bridge formed over the active site. This structural feature is suggested to stabilize the hydrolysis-productive acyl-enzyme species formed from the carbapenem substrates of this enzyme. Furthermore, our structural studies provide strong evidence that the hydroxyethyl group of carbapenems samples different orientations in the active sites of CHDLs, and the optimum orientation for catalysis depends on the topology of the active site allowing proper closure of the active site. We propose that CHDLs use the plasticity of the active site to drive the mechanism of carbapenem hydrolysis toward efficiency.

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“…In β-lactamases such as OXA-11 and OXA-15, the degradation substrate is extended to extended-spectrum cephalosporins (oxyimino-β-lactams), but not carbapenems, and they are classified as Bush-Jacoby functional subgroup 2de [46,47]. This type of β-lactamases is frequently encoded on plasmids and/ or integrons allowing for their wide dissemination [48]. Carbapenem-hydrolyzing class D β-lactamases (CHDLs) are OXA enzymes that hydrolyze carbapenems and belong to Bush-Jacoby functional subgroup 2df.…”

Section: Class D Esbl Oxacillinases (Oxas)mentioning

confidence: 99%

“…OXA enzymes with carbapenem-hydrolyzing activity have mainly been found on the chromosomes of Acinetobacter baumannii strains [49], but OXA-23 and OXA-48 have been reported on plasmids isolated from enteric bacteria [50,51]. These OXA-type enzymes are widespread across Acinetobacter, Shewanella, Pseudomonas, and Burkholderi [48,52]. At the time of writing, 790 OXA-variants could be found in public databases.…”

Section: Class D Esbl Oxacillinases (Oxas)mentioning

confidence: 99%

Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance

2020

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Along with the recent spread of multidrug-resistant bacteria, outbreaks of extended-spectrum β-lactamase (ESBL) and carbapenemase-producing bacteria present a serious challenge to clinicians. β-lactam antibiotics are the most frequently used antibacterial agents and ESBLs, and carbapenemases confer resistance not only to carbapenem antibiotics but also to penicillin and cephem antibiotics. The mechanism of β-lactam resistance involves an efflux pump, reduced permeability, altered transpeptidases, and inactivation by β-lactamases. Horizontal gene transfer is the most common mechanism associated with the spread of extended-spectrum β-lactamand carbapenem resistance among pathogenic bacterial species. Along with the increase in antimicrobial resistance, many different types of ESBLs and carbapenemases have emerged with different enzymatic characteristics. For example, carbapenemases are represented across classes A to D of the Ambler classification system. Because bacteria harboring different types of ESBLs and carbapenemases require specific therapeutic strategies, it is essential for clinicians to understand the characteristics of infecting pathogens. In this review, we summarize the current knowledge on carbapenem resistance by ESBLs and carbapenemases, such as class A carbapenemases, class C extended-spectrum AmpC (ESAC), carbapenem-hydrolyzing class D β-lactamases (CHDLs), and class B metallo-βlactamases, with the aim of aiding critical care clinicians in their therapeutic decision making.

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Acquired Class D β-Lactamases

Cited by 71 publications

References 180 publications

Identification of the OXA-48 Carbapenemase Family by Use of Tryptic Peptides and Liquid Chromatography-Tandem Mass Spectrometry

Identification of the OXA-48 Carbapenemase Family by Use of Tryptic Peptides and Liquid Chromatography-Tandem Mass Spectrometry

Active-Site Plasticity Is Essential to Carbapenem Hydrolysis by OXA-58 Class D β-Lactamase of Acinetobacter baumannii

Molecular diversity of extended-spectrum β-lactamases and carbapenemases, and antimicrobial resistance

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