Competitive inhibitors of the CphA metallo-beta-lactamase from Aeromonas hydrophila

in Antimicrobial Agents and Chemotherapy (2007), 51(6), 2136-2142

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 ... [more ▼]

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 members. The present work reveals that certain pyridine carboxylates are competitive inhibitors of CphA, a subclass B2 enzyme. X-ray crystallographic analyses demonstrate that pyridine-2,4-dicarboxylic acid chelates the zinc ion in a bidentate manner within the active site. Salts of these compounds are already available and undergoing biomedical testing for various nonrelated purposes. Pyridine carboxylates appear to be useful templates for the development of more-complex, selective, nontoxic inhibitors of subclass B2 metallo-beta-lactamases. [less ▲]

The structures and catalytic mechanisms of active-site serine beta-lactamases.

in Biotechnology & Genetic Engineering Reviews (1994), 12

Structure du 8-chloro-11-(méthylpipérazin-1-yl)dibenzo[b,f]-1,4-thiazépine

in Acta Crystallographica Section C-Crystal Structure Communications (1992), C48

Comparison of the Sequences of Class a Beta-Lactamases and of the Secondary Structure Elements of Penicillin-Recognizing Proteins

in Antimicrobial Agents and Chemotherapy (1991), 35(11), 2294-2301

The sequences of class A beta-lactamases were compared. Four main groups of enzymes were distinguished: those from the gram-negative organisms and bacilli and two distinct groups of Streptomyces spp. The ... [more ▼]

The sequences of class A beta-lactamases were compared. Four main groups of enzymes were distinguished: those from the gram-negative organisms and bacilli and two distinct groups of Streptomyces spp. The Staphylococcus aureus PC1 enzyme, although somewhat closer to the enzyme from the Bacillus group, did not belong to any of the groups of beta-lactamases. The similarities between the secondary structure elements of these enzymes and those of the class C beta-lactamases and of the Streptomyces sp. strain R61 DD-peptidase were also analyzed and tentatively extended to the class D beta-lactamases. A unified nomenclature of secondary structure elements is proposed for all the penicillin-recognizing enzymes. [less ▲]

Structure du méthyl-4 pipérazinyl-1)-10 pyrido[4,3-b][1,4]benzothiazépine

in Acta Crystallographica Section C-Crystal Structure Communications (1991), C47

Structure de l'acide (tert-butylamino-4 oxo-5 triazol-1,2,4 yle-1)acétique

in Acta Crystallographica (1991), C47

Structure du [4-phénylacétylimino-1-(1,2,4-triazolio)]acétate de sodium dihydrate

in Acta Crystallographica (1991), C47

Engineering a Novel Beta-Lactamase by a Single Point Mutation

in Protein Engineering (1990), 4(1), 79-86

beta-Lactamases are widespread and efficient bacterial enzymes which play a major role in bacterial resistance to penicillins and cephalosporins. In order to elucidate the role of the residues lying in a ... [more ▼]

beta-Lactamases are widespread and efficient bacterial enzymes which play a major role in bacterial resistance to penicillins and cephalosporins. In order to elucidate the role of the residues lying in a conserved loop of the enzymatic cavity of the active-site serine Streptomyces albus G beta-lactamase, modified proteins were produced by oligo-directed mutagenesis. Mutation of Asn116, which lies on one side of the active site cavity pointing to the substrate-binding site, into a serine residue resulted in spectacular modifications of the specificity profile of the enzyme. That replacement yielded an enzyme with a nearly unchanged activity towards good penicillin substrates. In sharp contrast its efficiency in hydrolysing cephalosporins was drastically reduced, the best substrates suffering the largest decrease in the second-order rate constant for serine acylation. In fact that single mutation generated a truly new enzyme behaving exclusively as a penicillinase, a situation which is never encountered to the same degree in any of the numerous naturally occurring variants of class A beta-lactamases. [less ▲]

Beta-lactamase of Bacillus licheniformis 749/C at 2 A resolution.

in Proteins (1990), 7(2), 156-71

Two crystal forms (A and B) of the 29,500 Da Class A beta-lactamase (penicillinase) from Bacillus licheniformis 749/C have been examined crystallographically. The structure of B-form crystals has been ... [more ▼]

Two crystal forms (A and B) of the 29,500 Da Class A beta-lactamase (penicillinase) from Bacillus licheniformis 749/C have been examined crystallographically. The structure of B-form crystals has been solved to 2 A resolution, the starting model for which was a 3.5 A structure obtained from A-form crystals. The beta-lactamase has an alpha + beta structure with 11 helices and 5 beta-strands seen also in a penicillin target DD-peptidase of Streptomyces R61. Atomic parameters of the two molecules in the asymmetric unit were refined by simulated annealing at 2.0 A resolution. The R factor is 0.208 for the 27,330 data greater than 3 sigma (F), with water molecules excluded from the model. The catalytic Ser-70 is at the N-terminus of a helix and is within hydrogen bonding distance of conserved Lys-73. Also interacting with the Lys-73 are Asn-132 and the conserved Glu-166, which is on a potentially flexible helix-containing loop. The structure suggests the binding of beta-lactam substrates is facilitated by interactions with Lys-234, Thr-235, and Ala-237 in a conserved beta-strand peptide, which is antiparallel to the beta-lactam's acylamido linkage; an exposed cavity near Asn-170 exists for acylamido substituents. The reactive double bond of clavulanate-type inhibitors may interact with Arg-244 on the fourth beta-strand. A very similar binding site architecture is seen in the DD-peptidase. [less ▲]

Structure de la bétaïne phénylacétylamino-5 thiazolium acétate-3 2,63 hydrate

in Acta Crystallographica (1989), C45