Carbapenem Resistance in Elizabethkingia meningoseptica Is Mediated by Metallo-β-Lactamase BlaB

González, Lisandro J.; Vila, Alejandro J.

doi:10.1128/aac.05835-11

Cited by 77 publications

(59 citation statements)

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“…GOB is also peculiar in that its native organism, E. meningoseptica, is the only known bacterium expressing two MBLs: the B1 enzyme BlaB and the B3 enzyme GOB. We have shown that even if both genes are actively expressed, the higher levels of BlaB make this enzyme the one responsible for carbapenemase resistance (33). Thus, GOB could be redundant in this organism despite its efficient catalytic performance.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, GOB enzymes present a divergent metal binding site with novel substrate binding features which make them unique among B3 MBLs. This observation, together with the finding that the resistance profile of E. meningoseptica is elicited mostly by the B1 enzyme BlaB (33), discloses a functional redundancy and suggests that GOB enzymes play alternative roles in this microorganism that have yet to be disclosed.…”

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confidence: 92%

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Crystal Structure of the Metallo-β-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site

Morán-Barrio

Lisa

Larrieux

et al. 2016

Antimicrob Agents Chemother

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f Metallo-beta-lactamases (MBLs) are broad-spectrum, Zn(II)-dependent lactamases able to confer resistance to virtually every ␤-lactam antibiotic currently available. The large diversity of active-site structures and metal content among MBLs from different sources has limited the design of a pan-MBL inhibitor. GOB-18 is a divergent MBL from subclass B3 that is expressed by the opportunistic Gram-negative pathogen Elizabethkingia meningoseptica. This MBL is atypical, since several residues conserved in B3 enzymes (such as a metal ligand His) are substituted in GOB enzymes. Here, we report the crystal structure of the periplasmic di-Zn(II) form of GOB-18. This enzyme displays a unique active-site structure, with residue Gln116 coordinating the Zn1 ion through its terminal amide moiety, replacing a ubiquitous His residue. This situation contrasts with that of B2 MBLs, where an equivalent His116Asn substitution leads to a di-Zn(II) inactive species. Instead, both the mono-and di-Zn(II) forms of GOB-18 are active against penicillins, cephalosporins, and carbapenems. In silico docking and molecular dynamics simulations indicate that residue Met221 is not involved in substrate binding, in contrast to Ser221, which otherwise is conserved in most B3 enzymes. These distinctive features are conserved in recently reported GOB orthologues in environmental bacteria. These findings provide valuable information for inhibitor design and also posit that GOB enzymes have alternative functions.T he expression of ␤-lactamases is the main mechanism of bacterial resistance against ␤-lactam antibiotics. These enzymes catalyze the hydrolysis of the amide bond in the ␤-lactam ring characteristic of this family of drugs (1-5). MBLs are metal-dependent hydrolases which generally use Zn(II) as a Lewis acid to activate a water molecule for the nucleophilic attack. These enzymes are refractive to clinically employed lactamase inhibitors (1) and have a particular relevance in the clinical setting as they can hydrolyze a broad spectrum of ␤-lactam substrates, being able to inactivate carbapenems, the "last-resort" antibiotics in antibacterial therapy (6).MBLs have been classified into subclasses B1, B2, and B3 based on sequence identity (7). Crystal structures of MBLs from the three subclasses have revealed that these enzymes present a common ␣␤/␤␣ sandwich fold, with the active site located within a groove at the interface between these two halves (1-6). The Zn(II)-binding residues vary among different subclasses, giving rise to diverse metal site architectures and metal contents required for activity (1-6). B1 and B3 MBLs are broad-spectrum enzymes that hydrolyze penicillins, cephalosporins, and carbapenems with a wide variety of in vitro catalytic efficiencies, displaying a broad range of resistance profiles in vivo (1)(2)(3)(4)(5)8). The di-Zn(II) form of B1 MBLs has been shown to be the active form in the bacterial periplasm, despite contradictory data obtained from in vitro studies (8-10). These enzymes display a conserved metal binding m...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

Crystal Structure of the Metallo-β-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site

Morán-Barrio

Lisa

Larrieux

et al. 2016

Antimicrob Agents Chemother

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“…(Docquier et al, 2002;Aubron et al, 2005;Girlich et al, 2010b;Henriques et al, 2012). Functional metagenomics studies have disclosed carbapenemase orthologs from bacteria in an Alaskan soil never inhabited by humans highlighting the huge pool of carbapenem resistance genes in the environment, which seems to predate the introduction of carbapenems in the therapeutic arsenal (Allen et al, 2009;Gonzalez and Vila, 2012). Environmental bacterial species carrying acquired CP genes have also been reported (Scotta et al, 2011).…”

Section: 72mentioning

confidence: 99%

Scientific Opinion on Carbapenem resistance in food animal ecosystems

Publication¹

2013

EFS2

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Carbapenems are broad-spectrum β-lactam antimicrobials used for the treatment of serious infections in humans. To date only sporadic studies have reported the occurrence of carbapenemase-producing (CP) bacteria in foodproducing animals and their environment. The bacteria and enzymes isolated include VIM-1 producing Escherichia coli and Salmonella Infantis from pigs and poultry in Germany, OXA-23-producing Acinetobacter spp. from cattle and horses in France and Belgium, and NDM-producing Acinetobacter spp. from pigs and poultry in China. In the German S. Infantis and E. coli isolates, the VIM-1-encoding genes were located on IncHI2 plasmids. A methodology including selective culture is proposed for the detection of CP strains of Enterobacteriaceae and Acinetobacter spp. The choice of selective media for the surveillance of carbapenem resistance for testing animal and food samples needs to be experimentally evaluated and validated. Biochemical and phenotypic tests for the confirmatory identification of CP bacteria are available. For CP bacteria in animals and food, active/passive monitoring and/or targeted surveys should cover key zoonotic agents, animal pathogens and indicator organisms. Priority should be given to broilers, fattening turkeys, fattening pigs, veal calves and meat thereof. Because there are no data on the comparative efficacy of individual control options, prioritisation is complex. Continued prohibition of the use of carbapenems in food-producing animals would be a simple and effective option. As genes encoding carbapenemase production are mostly plasmid-mediated, and co-resistance may be an important issue in the spread of such resistance mechanisms, decreasing the frequency of use of antimicrobials in animal production in the EU in accordance with prudent use guidelines is also of high priority. The effectiveness of any control measures should be monitored by targeted surveys, using selective isolation methods and pre-enrichment of samples. Control measures should be proactively implemented at national and international levels to prevent CP strains become widespread in livestock. SUMMARYThe European Food Safety Authority (EFSA) asked the Panel on Biological Hazards (BIOHAZ) to provide a scientific opinion on the carbapenem resistance in food animal ecosystems. Carbapenems are broad-spectrum beta (β)-lactam antimicrobials mostly used for the treatment of serious infections in humans, frequently in hospitalised patients, and are considered last-line therapy for infections caused by multidrug-resistant Gram-negative bacteria. In particular, the panel was asked: (i) to define the carbapenemase-producing (CP) bacterial strains and genes relevant for public health and linked to food-producing animals or food-borne transmission; (ii) to review the information on the epidemiology of acquired resistance to carbapenems, including the genes coding for such resistance, in food-producing animals and food; (iii) to perform a critical analysis of the methods (phenotypic and genotypic) and the interpr...

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“…In all previously reported clinical cases (6-8), E. anophelis isolates were resistant to most antibiotics recommended for empirical therapy, including third-generation cephalosporins, aminoglycosides and carbapenems (9), probably accounting for the poor infection outcomes. Consistently, most E. anophelis genomes harbor multiple antimicrobial resistance genes, including the two metallo-betalactamase genes bla GOB and bla blaB , associated with resistance to carbapenems (10). Currently, the clinical significance and biological distribution of E. anophelis is restricted, as this novel species is not well distinguished from other Elizabethkingia species in routine microbiological identification procedures, and as reference identification of E. anophelis relies mostly on the low-resolution 16S rRNA gene.…”

Section: Introductionmentioning

confidence: 99%

Genomic epidemiology and global diversity of the emerging bacterial pathogenElizabethkingia anophelis

Breurec

Criscuolo

Diancourt

et al. 2016

Preprint

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Elizabethkingia anophelis is an emerging pathogen involved in human infections and outbreaks in distinct world regions. We investigated the phylogenetic relationships and pathogenesis-associated genomic features of two neonatal meningitis isolates isolated 5 years apart from one hospital in Central African Republic and compared them with Elizabethkingia from other regions and sources. Average nucleotide identity firmly confirmed that E. anophelis, E. meningoseptica and E. miricola represent demarcated genomic species. A core genome multilocus sequence typing scheme, broadly applicable to Elizabethkingia species, was developed and made publicly available (http://bigsdb.pasteur.fr/ elizabethkingia). Phylogenetic analysis revealed distinct E. anophelis sublineages and demonstrated high genetic relatedness between the African isolates, compatible with persistence of the strain in the hospital environment. CRISPR spacer variation between the African isolates was mirrored by the presence of a large mobile genetic element. The pan-genome of E. anophelis comprised 6,880 gene families, underlining genomic heterogeneity of this species. African isolates carried unique resistance genes acquired by horizontal transfer. We demonstrated the presence of extensive variation of the capsular polysaccharide synthesis gene cluster in E. anophelis. Our results demonstrate the dynamic evolution of this emerging pathogen and the power of genomic approaches for Elizabethkingia identification, population biology and epidemiology.

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Carbapenem Resistance in Elizabethkingia meningoseptica Is Mediated by Metallo-β-Lactamase BlaB

Cited by 77 publications

References 50 publications

Crystal Structure of the Metallo-β-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site

Crystal Structure of the Metallo-β-Lactamase GOB in the Periplasmic Dizinc Form Reveals an Unusual Metal Site

Scientific Opinion on Carbapenem resistance in food animal ecosystems

Genomic epidemiology and global diversity of the emerging bacterial pathogenElizabethkingia anophelis

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