Molecular evolution of a class C β-lactamase extending its substrate specificity.

Nukaga, Michiyoshi; Haruta, Shin; Tanimoto, Kyoko; Kogure, Keiko; Taniguchi, Koki; Tamaki, Masaharu; Sawai, Tesuo

doi:10.1074/jbc.270.36.21428

Cited by 13 publications

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“…1, the deduced peptide sequences contained the SXSK motif characteristic of serine active site β‐lactamases [12] and three structural elements found in class C β‐lactamases: YXN, KTG and DAQA [12,22]. The tetrad DAQA, although more variable between the AmpC β‐lactamases, typically DAEA or DAES, was conserved in the six E. cloacae strains [3,17,19,23] and was also found in Ochrobacterium anthropi strains [24,25].…”

Section: Resultsmentioning

confidence: 97%

“…Enterobacter cloacae is the third most prevalent bacterium isolated in intensive care settings [1] and naturally exhibits resistance to first and second generation cephalosporins and to aminopenicillins, through a mechanism mediated by the production of an AmpC, Ambler class C β‐lactamase (Bush group 1) [1–7]. The production of AmpC cephalosporinases is of major concern since it confers resistance to most β‐lactams, sparing only carbapenems and ‘fourth generation’ cephalosporins [1,8].…”

Section: Introductionmentioning

confidence: 99%

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Diversity of chromosomal AmpC Î²-lactamases fromEnterobacter cloacaeisolates in a Portuguese hospital

Conceição¹,

Faria²,

Lito

et al. 2004

FEMS Microbiology Letters

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Six clinical isolates of Enterobacter cloacae isolated in a Portuguese hospital, between April 1999 and November 2000, demonstrated resistance to almost all broad-spectrum cephalosporins, except to cefepime. These isolates were susceptible to quinolones and to aminoglycosides. Isoelectric focusing demonstrated production of beta-lactamases with pIs > 8.0 and by all six isolates, exhibiting a cephalosporinase phenotype. The results of pulsed field gel electrophoresis revealed that these isolates were genetically unrelated. The amino acid sequence of six AmpC beta-lactamases (Eclo1FF, Eclo6FF, Eclo9FF, Eclo10FF, Eclo11FF and Eclo15FF) shared 97-99% homology with the chromosomal AmpC beta-lactamase from E. cloacae P99 and 86-87% homology with those of two plasmid-mediated AmpC beta-lactamases, MIR-1 and ACT-1. This is the first report of chromosomal AmpC beta-lactamase production by E. cloacae isolates in a Portuguese hospital.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Diversity of chromosomal AmpC Î²-lactamases fromEnterobacter cloacaeisolates in a Portuguese hospital

Conceição¹,

Faria²,

Lito

et al. 2004

FEMS Microbiology Letters

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“…The final consequences of the observed mutation on the 3D structure of the enzyme is difficult to determine. Extended spectrum AmpC β‐lactamases with resistance to oxyimino‐cephalosporins have been reported once from a clinical isolate of E. cloacae GC1 [8,30]. The mutation corresponded to a three amino acid insertion, AVR, in the omega loop of the β‐lactamase (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The amino acid sequence deduced from the ampC nucleotide sequence was compared with those from various isolates of E. cloacae corresponding to MHN1 [28], MHN1 mutant [17], P99 [28], P99 mutant [18], GC1 [8] and Q908R [28]. The most remarkable feature of the CHE AmpC was a six amino acid deletion, SKVALA, at positions 289–294 of the mature protein, corresponding to a deletion of 18 nucleotides in the gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mutation, deletion or insertion in only one of these genes, ampD , results in constitutive overproduction of the enzyme and resistance to third‐generation cephalosporins [5]. Resistance to these β‐lactams may also be mediated by mutations in the ampR gene, resulting in production of more active transcriptional activator, or in the structural ampC gene, extending the substrate specificity of the β‐lactamase [6–8]. Cefepime and cefpirome rapidly penetrate into Gram‐negative bacteria, have a high affinity for essential penicillin‐binding protein and are stable to attack from chromosome‐encoded β‐lactamases [9–12].…”

Section: Introductionmentioning

confidence: 99%

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Extension of resistance to cefepime and cefpirome associated to a six amino acid deletion in the H-10 helix of the cephalosporinase of anEnterobacter cloacaeclinical isolate

Barnaud

Labia

Raskine

et al. 2001

FEMS Microbiology Letters

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Enterobacter cloacae CHE, a clinical strain with overproduced cephalosporinase was found to be highly resistant to the new cephalosporins, cefepime and cefpirome (MICs> or =128 microg ml(-1)). The strain was isolated from a child previously treated with cefepime. The catalytic efficiency of the purified enzyme with the third-generation cephalosporins, cefepime and cefpirome, was 10 times higher than that with the E. cloacae P99 enzyme. This was mostly due to a decrease in K(m) for these beta-lactams. The clinical isolate produced large amounts of the cephalosporinase because introduction of the ampD gene decreased ampC expression and partially restored the wild-type phenotype. Indeed, MICs of cefepime and cefpirome remained 10 times higher than those for a stable derepressed clinical isolate (OUDhyp) transformed with an ampD gene. Sequencing of the ampC gene showed that 18 nucleotides had been deleted, corresponding to the six amino acids SKVALA (residues 289--294). According to the crystal structure of P99 beta-lactamase, this deletion was located in the H-10 helix. The ampR-ampC genes from the clinical isolates CHE and OUDhyp were cloned and expressed in Escherichia coli JM101. The MICs of cefpirome and cefepime of E. coli harboring ampC and ampR genes from CHE were 100--200 times higher than those of E. coli harboring ampC and ampR genes from OUDhyp. This suggests that the deletion, confirmed by sequencing of the ampC gene, is involved in resistance to cefepime and cefpirome. However, the high level of resistance to cefepime and cefpirome observed in the E. cloacae clinical isolate was due to a combination of hyperproduction of the AmpC beta-lactamase and structural modification of the enzyme. This is the first example of an AmpC variant conferring resistance to cefepime and cefpirome, isolated as a clinical strain.

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New definitions of extended‐spectrum β‐lactamase conferring worldwide emerging antibiotic resistance

Lee

Bae

Lee

2011

Medicinal Research Reviews

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Although there is no consensus of the precise definition of ESBL, three kinds of ESBL definitions have been proposed. First, the classical definition includes variants derived from TEM-1, TEM-2, or SHV-1; K1 (KOXY) of Klebsiella oxytoca. Second, the broadened definition has stretched the classical definition of ESBL to include: (1) β-lactamases (CTX-M-ESBLs, GES-ESBLs, and VEB-ESBLs), with spectra similar to those of TEM and SHV variants (designated as TEM- and SHV-ESBLs, respectively) but derived from other sources; (2) TEM and SHV variants with borderline ESBL activity; e.g., TEM-12; and (3) various β-lactamases conferring wider resistance than their parent types but not meeting the definition for group 2be; e.g., OXA-types (OXA-ESBLs) and mutant AmpC-types (AmpC-ESBLs), with increased activity against oxyimino-cephalosporins and with resistance to clavulanic acid. Third, the all-inclusive definition includes: (1) ESBL(A) (named for class A ESBLs); (2) ESBL(M) (miscellaneous ESBLs), which has been subdivided into ESBL(M-C) (class C; plasmid-mediated AmpC) and ESBL(M-D) (class D); and (3) ESBL(CARBA) (ESBLs with hydrolytic activity against carbapenems), which has been subdivided into ESBL(CARBA-A) (class A carbapenemases), ESBL(CARBA-B) (class B carbapenemases), and ESBL(CARBA-D) (class D carbapenemases). The consensus view about the ESBL definition is that the classical ESBL definition must be expanded to class A non-TEM- and non-SHV-ESBLs (CTX-M-, GES-, VEB-ESBLs, etc.). However, these three definitions evoke rational debate on the question "Which would be included in the category of ESBLs among AmpC-ESBLs, OXA-ESBLs, and/or carbapenemases?" Therefore, there is a great need for consensus in the precise definition of ESBL.

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Molecular evolution of a class C β-lactamase extending its substrate specificity.

Cited by 13 publications

References 0 publications

Diversity of chromosomal AmpC Î²-lactamases fromEnterobacter cloacaeisolates in a Portuguese hospital

Diversity of chromosomal AmpC Î²-lactamases fromEnterobacter cloacaeisolates in a Portuguese hospital

Extension of resistance to cefepime and cefpirome associated to a six amino acid deletion in the H-10 helix of the cephalosporinase of anEnterobacter cloacaeclinical isolate

New definitions of extended‐spectrum β‐lactamase conferring worldwide emerging antibiotic resistance

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