SHV-49, a Novel Inhibitor-Resistant β-Lactamase in a Clinical Isolate of
            <i>Klebsiella pneumoniae</i>

Dubois, Véronique; Poirel, Laurent; Arpin, Corinne; Coulange, Laure; Bebear, Cécile; Nordmann, Patrice; Quentin, Claudine

doi:10.1128/aac.48.11.4466-4469.2004

Cited by 29 publications

(33 citation statements)

References 25 publications

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“…(385). IR SHVs have also been isolated from K. pneumoniae, with a total of five IR SHVs presently described (Table 5) (109). Operationally, inhibitor resistance refers to resistance to amoxicillin-clavulanate and may, but does not necessarily, include resistance to sulbactam and tazobactam (410).…”

Section: Inhibitor-resistant Class a ␤-Lactamasesmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

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Section: Inhibitor-resistant Class a ␤-Lactamasesmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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“…Inhibitor-resistant (IR) TEM-type enzymes conferring amoxicillin-clavulanate resistance and cephalothin susceptibility (2,3,8,10) and expanded-spectrum ␤-lactamases conferring expanded-spectrum cephalosporin resistance (5) have been described in K. pneumoniae and other Enterobacteriaceae. SHV mutant enzymes are mainly expanded-spectrum ␤-lactamases (21); however, rare IR-SHV-type ␤-lactamases (SHV-10 and SHV-49) have been identified (6,16). We report here SHV-56, the third variant of the SHV family to exhibit resistance to inhibitors, from a K. pneumoniae clinical strain.…”

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confidence: 99%

“…bla SHV-56 differed from bla SHV-1 (4) by seven nucleotide substitutions that lead to two amino acid substitutions, Leu353Gln and Lys2343Arg, according to the Ambler nomenclature (1). The Leu353Gln substitution is frequently encountered and characteristic of the SHV-11 enzyme, which is a broad-spectrum ␤-lactamase inhibited with a low K i by clavulanate (6,12). The Lys2343Arg substitution has not been reported so far, and its role was investigated, especially with regard to ␤-lactamase inhibitor susceptibility.…”

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confidence: 99%

Molecular and Biochemical Characterization of SHV-56, a Novel Inhibitor-Resistant β-Lactamase fromKlebsiella pneumoniae

Dubois

Poirel

Demarthe

et al. 2008

Antimicrob Agents Chemother

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“…Alterations at M69 have been described in many TEM-type inhibitor resistant variants and recently an M69I variant in SHV (SHV-49) was observed clinically (24). This SHV variant had previously been shown to increase resistance to clavulanic acid and to a lesser degree resistance to sulbactam and tazobactam in laboratory constructs of SHV and the 94% sequence identical OHIO-1 (25-27).…”

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Effect of the Inhibitor-Resistant M69V Substitution on the Structures and Populations of trans-Enamine β-Lactamase Intermediates

et al. 2006

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The objective of this study is to determine the molecular factors that lead to β-lactamase inhibitor resistance for the variant M69V in SHV-1 β-lactamase. With mechanism-based inhibitors, the β-lactamase forms an acyl-enzyme that consists of a trans-enamine derivative in the active site. The present study focuses on these intermediates by introducing the mutation E166A that greatly retards deacylation. Thus, by comparing the properties of the E166A and the M69V-E166A forms we can explore the consequences of the resistance mutation at the level of the enamine acyl-enzymes. The reactions between the β-lactamase and the inhibitors tazobactam, sulbactam and clavulanic acid are followed in single crystals of the enzymes by using a Raman microscope. The resulting Raman difference spectroscopic data provide detailed information on conformational events involving the enamine species as well as an estimate of their populations. The Raman difference spectra for each of the inhibitors in the E166A and the M69V-E166A variants are very similar. In particular, detailed analysis of the main enamine Raman vibration near 1595 cm −1 reveals that the structure and flexibility of the enamine fragments are essentially identical for each of the three inhibitors in E166A and in the M69V-E166A double mutant. This finding is in accord with the X-ray derived structures, presented herein at 1.6 to 1.75 Å resolution, of the trans-enamine intermediates formed by the three inhibitors in M69V-E166A. However, a comparison of Raman results for M69V-E166A and E166A, show that the M69V mutation results in a 40%, 25% or negligible reduction in enamine population when the β-lactamase crystals are soaked in 5mM tazobactam, clavulanic acid and sulbactam solutions, respectively. The levels of enamine from tazobactam and clavulanic acid can be raised by increasing the concentrations of inhibitor in the mother liquor. Thus, the sensitivity of population levels to concentration of inhibitor in the mother liquor focuses attention on the properties of the encounter complex preceding acylation. It is proposed that for small ligands, such as tazobactam, sulbactam and clavulanic acid, the positioning of the lactam ring in the active site in the correct orientation for acylation is only one of a number of poorly defined conformations. For tazobactam and clavulanic acid the correctly oriented encounter complex is even less likely in the M69V variant leading to a reduction in inhibition of the enzyme via formation of the acyl-enzyme and the onset of resistance. Analysis of the X-ray structures of the three intermediates in M69V-E166A demonstrates that, compared to the structures for the E166A form, the oxyanion hole becomes smaller providing one explanation as to why acylation may be less efficient following the M69V substitution.β-lactamases (E.C.3.5.2.6) are a major mechanism of defense used by bacteria to protect themselves against the lethal action of β-lactam antibiotics (1). β-Lactamase enzymes are classified into four major classes, Ambler class A...

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SHV-49, a Novel Inhibitor-Resistant β-Lactamase in a Clinical Isolate of Klebsiella pneumoniae

Cited by 29 publications

References 25 publications

Three Decades of β-Lactamase Inhibitors

Three Decades of β-Lactamase Inhibitors

Molecular and Biochemical Characterization of SHV-56, a Novel Inhibitor-Resistant β-Lactamase fromKlebsiella pneumoniae

Effect of the Inhibitor-Resistant M69V Substitution on the Structures and Populations of trans-Enamine β-Lactamase Intermediates

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