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At least 1,063 records · Page 59Linked to original sources
PubMed1999

Inhibition of the broad spectrum nonmetallocarbapenamase of class A (NMC-A) beta-lactamase from Enterobacter cloacae by monocyclic beta-lactams.

beta-Lactamases hydrolyze beta-lactam antibiotics, a reaction that destroys their antibacterial activity. These enzymes, of which four classes are known, are the primary cause of resistance to beta-lactam antibiotics. The class A beta-lactamases form the largest group. A novel class A beta-lactamase, named the nonmetallocarbapenamase of class A (NMC-A) beta-lactamase, has been discovered recently that has a broad substrate profile that included carbapenem antibiotics. This is a serious development, since carbapenems have been relatively immune to the action of these resistance enzymes. Inhibitors for this enzyme are sought. We describe herein that a type of monobactam molecule of our design inactivates the NMC-A beta-lactamase rapidly, efficiently, and irreversibly. The mechanism of inactivation was investigated by solving the x-ray structure of the inhibited NMC-A enzyme to 1.95 A resolution. The structure shed light on the nature of the fragmentation of the inhibitor on enzyme acylation and indicated that there are two acyl-enzyme species that account for enzyme inhibition. Each of these inhibited enzyme species is trapped in a distinct local energy minimum that does not predispose the inhibitor species for deacylation, accounting for the irreversible mode of enzyme inhibition. Molecular dynamics simulations provided evidence in favor of a dynamic motion for the acyl-enzyme species, which samples a considerable conformational space prior to the entrapment of the two stable acyl-enzyme species in the local energy minima. A discussion of the likelihood of such dynamic motion for turnover of substrates during the normal catalytic processes of the enzyme is presented.

Anti-Bacterial Agents↗
PubMed2004

Atomic resolution structures and solution behavior of enzyme-substrate complexes of Enterobacter cloacae PB2 pentaerythritol tetranitrate reductase. Multiple conformational states and implications for the mechanism of nitroaromatic explosive degradation.

The structure of pentaerythritol tetranitrate (PETN) reductase in complex with the nitroaromatic substrate picric acid determined previously at 1.55 A resolution indicated additional electron density between the indole ring of residue Trp-102 and the nitro group at C-6 of picrate. The data suggested the presence of an unusual bond between substrate and the tryptophan side chain. Herein, we have extended the resolution of the PETN reductase-picric acid complex to 0.9 A. This high-resolution analysis indicates that the active site is partially occupied with picric acid and that the anomalous density seen in the original study is attributed to the population of multiple conformational states of Trp-102 and not a formal covalent bond between the indole ring of Trp-102 and picric acid. The significance of any interaction between Trp-102 and nitroaromatic substrates was probed further in solution and crystal complexes with wild-type and mutant (W102Y and W102F) enzymes. Unlike with wild-type enzyme, in the crystalline form picric acid was bound at full occupancy in the mutant enzymes, and there was no evidence for multiple conformations of active site residues. Solution studies indicate tighter binding of picric acid in the active sites of the W102Y and W102F enzymes. Mutation of Trp-102 does not impair significantly enzyme reduction by NADPH, but the kinetics of decay of the hydride-Meisenheimer complex are accelerated in the mutant enzymes. The data reveal that decay of the hydride-Meisenheimer complex is enzyme catalyzed and that the final distribution of reaction products for the mutant enzymes is substantially different from wild-type enzyme. Implications for the mechanism of high explosive degradation by PETN reductase are discussed.

2,4-Dinitrophenol↗
PubMed1983

Nonspecific induction of beta-lactamase in Enterobacter cloacae.

Since the introduction of the new beta-lactamase-stable beta-lactam compounds, inducible beta-lactamases have become increasingly important clinically [1]. It has recently been pointed out that most beta-lactam antibiotics appear to be affected by these derepressed enzymes either by hydrolysis or by the nonhydrolytic barrier mechanism [2]. Until now, it has generally been assumed that beta-lactamases are induced only by the beta-lactam compounds themselves. We investigated an E cloacae strain that exhibited high levels of resistance to most beta-lactam antibiotics. (MICs were greater than 32 micrograms/ml, except for N-formimidoyl thienamycin and the penem compound Sch 29482). Spontaneous production of beta-lactamase (after overnight culture in Isosensitest broth) was only marginal. However, the induction potency of Schaedler's broth even exceeded that of cefoxitin, which is known to be a good inducer [2]. We evaluated the induction potency of various cyclic compounds, such as amino acids, vitamins, purine derivatives, and steroid hormones. Only tryptophane, thiamine, folic acid, and hemine proved to be effacious inducers. Consequently, we explored the possibility that biological fluids also exhibit induction potency. The addition of inactivated serum (at a concentration of 25%) to the Isosensitest medium led to an enzyme induction comparable to that of cefoxitin. Similar results could be obtained with the addition of pleural fluid, CSF, or urine. These observations confirm the previous report that Morganella morganii strains produced considerable amounts of beta-lactamase even in a group of animals that did not receive treatment with beta-lactam compounds (granuloma pouch model) [3].(ABSTRACT TRUNCATED AT 250 WORDS)

Enterobacter↗