Description of the metallo-β-lactamase GIM-1 in Acinetobacter pittii

Kaase, Martin; Szabados, Florian; Pfennigwerth, Niels; Anders, Agnes; Geis, G.; Pranada, Arthur B.; Rößler, Susann; Lang, Uwe; Gatermann, Sören

doi:10.1093/jac/dkt325

Cited by 35 publications

(22 citation statements)

References 16 publications

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“…For carbapenemase detection, a modified Hodge test (7), as well as combined disk tests with EDTA (8) and boronic acid (9), were carried out. In addition, PCRs for KPC (10), VIM (8,11), IMP (8), NDM (12), and OXA-48 (13) were performed routinely. If the phenotypic tests suggested a carbapenemase that was not detected by PCR, the isolates were analyzed by a microbiological bioassay (14) and additional PCRs for rarely occurring carbapenemases, like GIM-1 (15).…”

Section: Strainsmentioning

confidence: 99%

Fosfomycin Susceptibility in Carbapenem-Resistant Enterobacteriaceae from Germany

Kaase

Szabados²,

Anders

et al. 2014

J Clin Microbiol

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bDue to the increase in multidrug-resistant Enterobacteriaceae, the interest in older antimicrobial agents, like fosfomycin, has increased. In this study, we used agar dilution for testing susceptibilities to fosfomycin in a collection of 107 carbapenem-nonsusceptible Enterobacteriaceae isolates, of which 80 produced various types of carbapenemases, including KPC, VIM, NDM, and OXA-48. Overall, 78% of the strains had fosfomycin MICs of <32 mg/liter and were thus considered to be susceptible according to the current EUCAST breakpoint. The MIC 50 and MIC 90 were 8 mg/liter and 512 mg/liter, respectively. Escherichia coli strains had significantly lower fosfomycin MICs than the Klebsiella pneumoniae and Enterobacter cloacae strains. Furthermore, comparisons of the susceptibility testing methods, like Etest and disk diffusion, were performed against agar dilution as the reference method. Essential agreement between Etest and agar dilution was 78.9%, and categorical agreement between the two methods was 92.5%, with 20% very major errors and 2.6% major errors. Disk diffusion was studied with 50-g and 200-g fosfomycin disks, but no inhibition zone breakpoint that reduced very major and major errors to an acceptable level was found. Etest and disk diffusion showed poor agreement with fosfomycin agar dilution.

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Section: Strainsmentioning

confidence: 99%

Fosfomycin Susceptibility in Carbapenem-Resistant Enterobacteriaceae from Germany

Kaase

Szabados²,

Anders

et al. 2014

J Clin Microbiol

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“…Recently, GIM-1 has been identified in other bacterial species, such as Serratia marcescens (7), Enterobacter cloacae (8), and Acinetobacter pittii (9), indicating that it is transmitted on mobile genetic elements (6,7). A new variant of GIM-1 (GIM-2) with a single mutation, A290G, was recently discovered (10).…”

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confidence: 99%

Role of Residues W228 and Y233 in the Structure and Activity of Metallo-β-Lactamase GIM-1

Skagseth

Carlsen

Bjerga

et al. 2016

Antimicrob Agents Chemother

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e Metallo-␤-lactamases (MBLs) hydrolyze virtually all ␤-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. The worldwide emergence of antibiotic-resistant bacteria harboring MBLs poses an increasing clinical threat. The MBL German imipenemase-1 (GIM-1) possesses an active site that is narrower and more hydrophobic than the active sites of other MBLs. The GIM-1 active-site groove is shaped by the presence of the aromatic side chains of tryptophan at residue 228 and tyrosine at residue 233, positions where other MBLs harbor hydrophilic residues. To investigate the importance of these two residues, eight site-directed mutants of GIM-1, W228R/A/Y/S and Y233N/A/I/S, were generated and characterized using enzyme kinetics, thermostability assays, and determination of the MICs of representative ␤-lactams. The structures of selected mutants were obtained by X-ray crystallography, and their interactions with ␤-lactam substrates were modeled in silico. Steady-state kinetics revealed that both positions are important to GIM-1 activity but that the effects of individual mutations vary depending on the ␤-lactam substrate. Activity against type 1 substrates bearing electron-donating C-3/C-4 substituents (cefoxitin, meropenem) could be enhanced by mutations at position 228, whereas hydrolysis of type 2 substrates (benzylpenicillin, ampicillin, ceftazidime, imipenem) with methyl or positively charged substituents was favored by mutations at position 233. The crystal structures showed that mutations at position 228 or the Y233A variant alters the conformation of GIM-1 loop L1 rather than that of loop L3, on which the mutations are located. Taken together, these data show that point mutations at both positions 228 and 233 can influence the catalytic properties and the structure of GIM-1. Members of the carbapenem class of ␤-lactams are among the most important antimicrobial agents available for the treatment of serious bacterial infections (1). However, their use against Gram-negative bacteria is now threatened by the dissemination of carbapenemases, ␤-lactamases that hydrolyze the amide bond of the ␤-lactam ring, thereby inactivating carbapenems and other ␤-lactams (2). To date, only a few effective carbapenemase inhibitors have been available for clinical use. Enzymes with carbapenemase activity have been identified in multiple ␤-lactamase classes. ␤-Lactamases are divided into four classes, of which classes A, C, and D are serine enzymes that catalyze hydrolysis of the ␤-lactam through a serine-bound acyl intermediate, whereas class B ␤-lactamases, or metallo-␤-lactamases (MBLs), coordinate one or two zinc ions in the active site, which are essential for their enzymatic activity (1-3). The class B MBLs can be divided into four subclasses, according to their primary structure: B1a (e.g., VIM, IMP, DIM, and SPM), B1b (NDM), B2 (e.g., CphA), and B3 (e.g., L1 and AIM) (3). Currently, no clinically effective MBL inhibitor has been approved for use (4). Avibactam, the only clinically approved effective carbap...

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“…Environmental sampling was conducted in the context of a protracted multispecies outbreak of GIM-1-producing bacteria, lasting over more than 10 years, in our hospital. This situation is unique, as GIM-1 is still locally restricted to Germany and rarely reported (10,(25)(26)(27)(28). Recently we were even able to describe a variant, GIM-2, in Düsseldorf (20).…”

Section: Discussionmentioning

confidence: 95%

“…We were also able to show the bla GIM-1 gene in a broad range of nonfermenter species typical of the aquatic environment: P. nitroreducens, P. oleovorans, A. bereziniae, A. hydrophila, and S. maltophilia. None of these species has been known to carry bla GIM-1 to date, as it has been described only in the nonfermenters P. aeruginosa, P. putida, and A. pittii (10,26,28). These bacteria have a lower clinical significance but may serve as a genetic reservoir of resistance.…”

Section: Discussionmentioning

confidence: 99%

Species Diversity of Environmental GIM-1-Producing Bacteria Collected during a Long-Term Outbreak

Wendel

Ressina

Kolbe-Busch

et al. 2016

Appl Environ Microbiol

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Reports of outbreaks concerning carbapenemase-producing Gram-negative bacteria in which the main source of transmission is the hospital environment are increasing. This study describes the results of environmental sampling in a protracted polyspecies metallo-beta-lactamase GIM-1 outbreak driven by plasmids and bacterial clones of Enterobacter cloacae and Pseudomonas aeruginosa in a tertiary care center. Environmental sampling targeting wet locations (especially sinks) was carried out on a surgical intensive care unit and on a medical ward on several occasions in 2012 and 2013. We were able to demonstrate 43 bla GIM-1 -carrying bacteria (mainly nonfermenters but also Enterobacteriaceae) that were either related or unrelated to clinical strains in 30 sinks and one hair washbasin. GIM-1 was found in 12 different species, some of which are described here as carriers of GIM-1. Forty out of 43 bacteria displayed resistance to carbapenems and, in addition, to various non-beta-lactam antibiotics. Colistin resistance was observed in two E. cloacae isolates with MICs above 256 mg/liter. The bla GIM-1 gene was harbored in 12 different class 1 integrons, some without the typical 3= end. The bla GIM-1 gene was localized on plasmids in five isolates. In vitro plasmid transfer by conjugation was successful in one isolate. The environment, with putatively multispecies biofilms, seems to be an important biological niche for multidrug-resistant bacteria and resistance genes. Biofilms may serve as a "melting pot" for horizontal gene transfer, for dissemination into new species, and as a reservoir to propagate future hospital outbreaks. IMPORTANCEIn Gram-negative bacteria, resistance to the clinically relevant broad-spectrum carbapenem antibiotics is a major public health concern. Major reservoirs for these resistant organisms are not only the gastrointestinal tracts of animals and humans but also the (hospital) environment. Due to the difficulty in eradicating biofilm formation in the latter, a sustained dissemination of multidrug-resistant bacteria from the environment can occur. In addition, horizontal transfer of resistance genes on mobile genetic elements within biofilms adds to the total "resistance gene pool" in the environment. To gain insight into the transmission pathways of a rare and locally restricted carbapenemases resistance gene (bla GIM-1 ), we analyzed the genetic background of the bla GIM-1 gene in environmental bacteria during a long-term polyspecies outbreak in a German hospital.

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Description of the metallo-β-lactamase GIM-1 in Acinetobacter pittii

Cited by 35 publications

References 16 publications

Fosfomycin Susceptibility in Carbapenem-Resistant Enterobacteriaceae from Germany

Fosfomycin Susceptibility in Carbapenem-Resistant Enterobacteriaceae from Germany

Role of Residues W228 and Y233 in the Structure and Activity of Metallo-β-Lactamase GIM-1

Species Diversity of Environmental GIM-1-Producing Bacteria Collected during a Long-Term Outbreak

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