Trifluoromethyl alcohol and ketone inhibitors of metallo-β-lactamases

Walter, Magnus W.; Felici, Antonio; Galleni, Moreno; Soto, Raquel Paul; Adlington, Robert M.; Baldwin, Jack E.; Frère, Jean‐Marie; Gololobov, Mikhail Yu.; Schofield, Christopher J.

doi:10.1016/0960-894x(96)00453-2

Cited by 89 publications

(51 citation statements)

References 22 publications

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“…The potential clinical significance of VIM-1 and the uniqueness of some of its functional properties render this enzyme a most interesting candidate for further studies of the molecular structure and the interaction with known metallo-␤-lactamase inhibitors (14,17,26,29). …”

Section: Discussionmentioning

confidence: 99%

Purification and Biochemical Characterization of the VIM-1 Metallo-β-Lactamase

Franceschini

Caravelli

Docquier

et al. 2000

Antimicrob Agents Chemother

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VIM-1 is a new group 3 metallo-␤-lactamase recently detected in carbapenem-resistant nosocomial isolates of Pseudomonas aeruginosa from the Mediterranean area. In this work, VIM-1 was purified from an Escherichia coli strain carrying the cloned bla VIM-1 gene by means of an anion-exchange chromatography step followed by a gel permeation chromatography step. The purified enzyme exhibited a molecular mass of 26 kDa in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and an acidic pI of 5.1 in analytical isoelectric focusing. Amino-terminal sequencing showed that mature VIM-1 results from the removal of a 26-amino-acid signal peptide from the precursor. VIM-1 hydrolyzes a broad array of ␤-lactam compounds, including penicillins, narrow-to expanded-spectrum cephalosporins, carbapenems, and mechanism-based serine-␤-lactamase inactivators. Only monobactams escape hydrolysis. The highest catalytic constant/K m ratios (>10 6 M ؊1 ⅐ s ؊1 ) were observed with carbenicillin, azlocillin, some cephalosporins (cephaloridine, cephalothin, cefuroxime, cefepime, and cefpirome), imipenem, and biapenem. Kinetic parameters showed remarkable variability with different ␤-lactams and also within the various penam, cephem, and carbapenem compounds, resulting in no clear preference of the enzyme for any of these ␤-lactam subfamilies. Significant differences were observed with some substrates between the kinetic parameters of VIM-1 and those of other metallo-␤-lactamases. Inactivation assays carried out with various chelating agents (EDTA, 1,10-o-phenanthroline, and pyridine-2,6-dicarboxylic acid) indicated that formation of a ternary enzyme-metal-chelator complex precedes metal removal from the zinc center of the protein and revealed notable differences in the inactivation parameters of VIM-1 with different agents.Production of ␤-lactamases is the most common mechanism of bacterial resistance to ␤-lactam antibiotics. Among the ␤-lactam-degrading enzymes, metallo-␤-lactamases are notable for their substrate profile, which always includes carbapenems and often most classes of ␤-lactams, and for their resistance to mechanism-based ␤-lactamase inactivators (3,4,20). Owing to these features, the emergence of acquired metallo-␤-lactamases in clinical isolates of major gram-negative pathogens, such as members of the family Enterobacteriaceae and Pseudomonas aeruginosa, is a most worrying development in the field of microbial drug resistance (12).VIM-1 is a new molecular class B metallo-␤-lactamase which has recently been identified in carbapenem-resistant isolates of Pseudomonas aeruginosa from various Italian hospitals (11, 13, 21) and from Greece (27). Like the bla IMP gene, which was the first acquired metallo-␤-lactamase determinant found in nosocomial isolates of various gram-negative species in Japan (1, 7, 8,16,24,25) , abstr. E-85, p. 193, 1998), the bla VIM-1 gene is carried on an integron-borne gene cassette (11) and has the potential for spreading among major bacterial pathogens. For this reason, bla VIM-1 is potentially...

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Section: Discussionmentioning

confidence: 99%

Purification and Biochemical Characterization of the VIM-1 Metallo-β-Lactamase

Franceschini

Caravelli

Docquier

et al. 2000

Antimicrob Agents Chemother

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“…Reactive trifluoromethyl ketones and alcohols, conjugated to a penicillin-like phenyl side chain, effectively inhibit MBLs from B. cereus, P. aeruginosa, S. maltophilia, and A. hydrophila in vitro, presumably by binding the active-site Zn 2ϩ ion (433,434). The crystal structure of a biphenyl tetrazole inhibitor, L-159,061 (Fig.…”

Section: Trifluoromethyl Ketones and Alcoholsmentioning

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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“…Because of the great interest in MBL inhibition, several classes of inhibitors have been described (17,18); these include phenazines (19), ketone derivatives of L-and D-alanine and trifluoromethyl alcohol (20), thioesters (21,22), biphenyl tetrazoles (23,24), amino acid-derived hydroxamates (25), thiols (26 -30), and tricyclic natural products (31). However, despite many of these having good inhibitory properties, only a few thiols have a broad spectrum of inhibition for MBLs.…”

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The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril

Garcia-Saez

Hopkins

Papamicaël³

et al. 2003

Journal of Biological Chemistry

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130

124

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The crystal structure of the class-B ␤-lactamase, BlaB, from the pathogenic bacterium, Chryseobacterium meningosepticum, in complex with the inhibitor, D-captopril, has been solved at 1.5-Å resolution. The enzyme has the typical ␣␤/␤␣ metallo-␤-lactamase fold and the characteristic two metal binding sites of members of the subclass B1, in which two Zn 2؉ ions were identified. D-Captopril, a diastereoisomer of the commercial drug, captopril, acts as an inhibitor by displacing the catalytic hydroxyl ion required for antibiotic hydrolysis and intercalating its sulfhydryl group between the two Zn 2؉ ions. Interestingly, D-captopril is located on one side of the active site cleft. The x-ray structure of the complex of the closely related enzyme, IMP-1, with a mercaptocarboxylate inhibitor, which also contains a sulfhydryl group bound to the two Zn 2؉ ions, shows the ligand to be located on the opposite side of the active site cleft. A molecule generated by fusion of these two inhibitors would cover the entire cleft, suggesting an interesting approach to the design of highly specific inhibitors.

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Trifluoromethyl alcohol and ketone inhibitors of metallo-β-lactamases

Cited by 89 publications

References 22 publications

Purification and Biochemical Characterization of the VIM-1 Metallo-β-Lactamase

Purification and Biochemical Characterization of the VIM-1 Metallo-β-Lactamase

Three Decades of β-Lactamase Inhibitors

The 1.5-Å Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril

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