Carbapenemases: the Versatile β-Lactamases

Queenan, Anne Marie; Bush, Karen

doi:10.1128/cmr.00001-07

Cited by 2,256 publications

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References 259 publications

(277 reference statements)

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“…1,2 However, the recent emergence of class A b-lactamases capable of hydrolyzing carbapenems threatens this class of b-lactam antibiotics. [3][4][5][6] One of these blactamases, KPC-2, is becoming a major healthcare threat in the United States and throughout the world. 5,7,8 KPC-2 manifests a very broad substrate profile including penicillins, extended-spectrum cephalosporins, cephamycins, and carbapenems.…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5][6] One of these blactamases, KPC-2, is becoming a major healthcare threat in the United States and throughout the world. 5,7,8 KPC-2 manifests a very broad substrate profile including penicillins, extended-spectrum cephalosporins, cephamycins, and carbapenems. 9,10 Moreover, Papp-Wallace et al showed that this enzyme is resistant to b-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam), which are typically given in combination with a b-lactam for the treatment of infections caused by b-lactamase producing pathogens.…”

Section: Introductionmentioning

confidence: 99%

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Elucidating the role of Trp105 in the KPC‐2 β‐lactamase

et al. 2010

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The molecular basis of resistance to b-lactams and b-lactam-b-lactamase inhibitor combinations in the KPC family of class A enzymes is of extreme importance to the future design of effective b-lactam therapy. Recent crystal structures of KPC-2 and other class A b-lactamases suggest that Ambler position Trp105 may be of importance in binding b-lactam compounds. Based on this notion, we explored the role of residue Trp105 in KPC-2 by conducting site-saturation mutagenesis at this position. Escherichia coli DH10B cells expressing the Trp105Phe, -Tyr, -Asn, and -His KPC-2 variants possessed minimal inhibitory concentrations (MICs) similar to E. coli cells expressing wild type (WT) KPC-2. Interestingly, most of the variants showed increased MICs to ampicillin-clavulanic acid but not to ampicillin-sulbactam or piperacillin-tazobactam. To explain the biochemical basis of this behavior, four variants (Trp105Phe, -Asn, -Leu, and -Val) were studied in detail. Consistent with the MIC data, the Trp105Phe b-lactamase displayed improved catalytic efficiencies, k cat /K m , toward piperacillin, cephalothin, and nitrocefin, but slightly decreased k cat /K m toward cefotaxime and imipenem when compared to WT b-lactamase. The Trp105Asn variant exhibited increased K m s for all substrates. In contrast, the Trp105Leu and -Val substituted enzymes demonstrated notably decreased catalytic efficiencies (k cat /K m ) for all substrates. With respect to clavulanic acid, the K i s and partition ratios were increased for the Trp105Phe, -Asn, and -Val variants. We conclude that interactions between Trp105 of KPC-2 and the b-lactam are essential for hydrolysis of substrates. Taken together, kinetic and molecular modeling studies define the role of Trp105 in b-lactam and b-lactamase inhibitor discrimination.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elucidating the role of Trp105 in the KPC‐2 β‐lactamase

et al. 2010

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“…Identification of ESBL production was performed by phenotypic testing based on demonstration of synergy between clavulanic acid and extendedspectrum cephalosporins [2]. Carbapenemase production was detected by the modified Hodge test, and MBL production was further detected by phenotypic methods based on the demonstration of synergy between imipenem and ethylene diamine tetra-acetic acid (EDTA) [specifically, a three-fold or greater decrease in the imipenem minimum inhibitory concentration (MIC) in the presence of EDTA] [3].…”

Section: Mdr Enterobacteriaceae Clinical Isolates Identified Betweenmentioning

confidence: 99%

“…Carbapenems, once considered the mainstay of therapy for systemic infections caused by Enterobacteriaceae isolates with multidrug resistance, may be found to be microbiologically inactive against contemporary isolates owing to the presence of various specific mechanisms of resistance. These include the expression of serine carbapenemases and metallo--lactamases (MBLs) or decreased porin expression in conjunction with extended-spectrum -lactamase (ESBL) or AmpC -lactamase production [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin

Falagas

Maraki

Karageorgopoulos

et al. 2010

International Journal of Antimicrobial Agents

159

107

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The advancing antimicrobial drug resistance among Enterobacteriaceae renders the evaluation of potential novel therapeutic options necessary. We sought to evaluate the in vitro antimicrobial activity of fosfomycin against multidrug-resistant (MDR) Enterobacteriaceae isolates. Antimicrobial susceptibility to fosfomycin and 12 additional antibiotics of MDR Enterobacteriaceae isolates collected between November 2007 and April 2009 at the University Hospital of Heraklion, Crete, Greece, was examined using the Etest method. A total of 152 MDR Enterobacteriaceae isolates were studied, including Klebsiella pneumoniae (76.3%), Escherichia coli (17.1%), Proteus mirabilis (4.6%) and other species (2.0%).Antimicrobial susceptibility rates were highest for fosfomycin (92.8%), tigecycline (92.1%) and colistin (73.0%) followed by imipenem (35.5%), tetracycline (20.4%), gentamicin (19.7%), trimethoprim/sulfamethoxazole (12.5%) and ciprofloxacin (10.5%). Of the 152 isolates, 85 (55.9%) were extensively drug-resistant (XDR), of which 78 (91.8%) remained susceptible to fosfomycin. Susceptibility to fosfomycin of the 79 carbapenemase-producing, 34 extended-spectrum -lactamase-producing and 24 metallo--lactamase-producing isolates was 94.9%, 94.1% and 83.3%, respectively. In conclusion, in this study fosfomycin exhibited good in vitro antimicrobial activity against MDR and XDR Enterobacteriaceae. We suggest further evaluation of the potential clinical utility of fosfomycin against infections caused by these pathogens.

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“…However, carbapenemases were originally described as species-specific, chromosomally encoded β-lactamases (Queenan and Bush, 2007), and environmental strains have repeatedly been identified as reservoirs for progenitors of globally disseminating plasmid-encoded carbapenemases. For example, Acinetobacter radioresistens has been identified as the source of a chromosomal blaOXA-23-like gene, which is currently widespread as a plasmid-encoded blaOXA-23 in Acinetobacter baumannii (Poirel et al, 2008).…”

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confidence: 99%