Competitive Inhibitors of the CphA Metallo- -Lactamase from Aeromonas hydrophila
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چکیده
Competitive Inhibitors of the CphA Metallo-Lactamase from Aeromonas hydrophila L. E. Horsfall,† G. Garau,† B. M. R. Liénard, O. Dideberg, C. J. Schofield, J. M. Frère, and M. Galleni* Centre d’Ingéniérie des Protéines, Université de Liège, Allée de 6 Aout B6, Sart-Tilman, Liège, Belgium; Institut de Biologie Structurale Jean-Pierre Ebel (CNRS/CEA/UJF), 41 Rue J. Horowitz, Grenoble 38100, France; and Chemistry Research Laboratory, 12 Mansfield Road, Oxford, United Kingdom
منابع مشابه
Coordination geometries of metal ions in d- or l-captopril-inhibited metallo-beta-lactamases.
d- and l-captopril are competitive inhibitors of metallo-beta-lactamases. For the enzymes from Bacillus cereus (BcII) and Aeromonas hydrophila (CphA), we found that the mononuclear enzymes are the favored targets for inhibition. By combining results from extended x-ray absorption fine structure, perturbed angular correlation of gamma-rays spectroscopy, and a study of metal ion binding, we deriv...
متن کاملCompetitive inhibitors of the CphA metallo-beta-lactamase from Aeromonas hydrophila.
Various inhibitors of metallo-beta-lactamases have been reported; however, none are effective for all subgroups. Those that have been found to inhibit the enzymes of subclass B2 (catalytically active with one zinc) either contain a thiol (and show less inhibition towards this subgroup than towards the dizinc members of B1 and B3) or are inactivators behaving as substrates for the dizinc family ...
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The Aeromonas hydrophila AE036 chromosome contains a cphA gene encoding a metallo-beta-lactamase which is highly active against carbapenem antibiotics such as imipenem. Here we show that the cphA gene product shares inhibitory similarities with a mammalian zinc peptidase, membrane dipeptidase (MDP; dehydropeptidase I). Both enzymes are able to hydrolyze imipenem and are inhibited by cilastatin....
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The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identificat...
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Among class B beta-lactamases, the subclass B2 CphA enzyme is characterized by a unique specificity profile. CphA efficiently hydrolyzes only carbapenems. In this work, we generated site-directed mutants that possess a strongly broadened activity spectrum when compared with the WT CphA. Strikingly, the N116H/N220G double mutant exhibits a substrate profile close to that observed for the broad s...
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