Beta-lactam hydrolysis

As already mentioned, Lippard and co-workers have also studied the -hydroxy dizinc unit found in metallohydrolases in a model system [Zn2L(/x-OI I)(/x-02PPh2)]2+, L = 2,7-bis [2-(2-pyridylethyl)-aminomethyl]-l,8-naphthyridine) 454 Hydrolysis of phosphodiesters and beta-lactams was studied and related to the PI nuclease and beta-lactamase enzymes. The dinuclear complex... 

Chemical or enzymatic hydrolysis of this compound allows to obtain large quantities of 7-aminocephalosporanic acid. A number of semisynthetic beta-lactam cephalosporin antibiotics were created by acylating the amino group of the last with various acid derivatives (analogous to the semisynthetic penicillin series) and currently there are about 25,000 of them, of which about 100 are used in medicine. Unlike penicillins, semisynthetic cephalosporins are synthesized not only by expanding the spectrum of various acids by which 7-aminocephalosporanic acid is acylated, but also by internal modifications of aminocephalosporanic nucleus (Rj and Rj). 

Unlike penicillins and cephalosporins, which have a side aminoacyl group joined to the beta-lactam ring, imipenem has a a-hydroxyethyl side chain. Significant resistance to hydrolysis by beta-lactamases is observed in this compound, evidently thanks to the fran -configuration of the side chain, while the side chain of penicillins and cephalosporins have a cis-configuration. 

Beta-lactamase inhibitors include clavulanic acid, sulbactam and tazobactam. They are structurally related to the beta-lactam antibiotics however the antibacterial activity of these compounds is very weak or negligible. They are strong inhibitors of bacterial beta-lactamases and can protect beta-lactam antibiotics from hydrolysis by these enzymes. 

Synthetic heparinoid polymers such as polyanionic polyesters containing sulfamate and carboxylate groups were synthesized by hydrolysis of p(N chloro-sulfonyl beta lactam) [475]. These materials possess anti-coagulant activity (although lower than heparin) presumably due to the similarity of functional groups of this material and those found in heparin. 

Kaminskaia, N. V., Spingler, B., Lippard, S. J., Hydrolysis of beta-lactam antibiotics catalyzed by dinuclear zinc(II) complexes Functional mimics of metallo-beta-lactamases. J. Am. Chem. Soc. 2000, 122, 6411-6422. 

Penicillins are susceptible to hydrolysis, as the highly reactive beta-lactam has a... 

Resistance to beta-lactams in clinical isolates is primarily due to the hydrolysis of the antibiotic by beta-lactamases. Mutational events resulting in the modification of PBPs or cellular permeability also can lead to beta-lactam resistance. Beta-lactamase inhibitors such as tazobactam inactivate beta-lactamase. 

A major problem in the conversion of Penicillin G into 6-APA is to keep the reactive beta-lactam amide bond intact upon the desired hydrolysis of the secondary amide bond (see Fig 2.32). 

The serine beta-lactamases work in a mechanism similar to serine proteases and esterases, where the Ser center performs a ring opening electrophilic attack on the beta-lactam ring. Water then enters the site and enables the hydrolysis of the enzyme drug intermediate. The inactive penicillin is released and the enzyme is ready to attack another ring. This group of beta-lactamases is by far the more clinically important form of drug inactivation. 

There have been approximately 800 PBPs identified thus far. These proteins have been divided into class A and class B proteins, depending primarily on the number of reactions the protein is capable of catalyzing. Class A PBPs are bifunctional and catalyze both the polymerization of the glycan subunits (GT) and the transpepditation (TP) of the peptide chains, whereas the Glass B PBPs are monofunctional and serve as transpeptidase enzymes only. Both classes of PBPs are susceptible to beta-lactam attack and inhibition. Once the PBP is acylated by the beta-lactam it is incapable of further hydrolysis of the covalent acyl-enzyme intermediate and transpeptidation is inhibited. 

A. Classification All penicillins are derivatives of 6-aminopenicillanic acid and contain a beta-lactam ring structure that is essential for antibacterial activity. PeniciUin subclasses have additional chemical substituents that confer differences in antimicrobial activity, susceptibility to acid and enzymic hydrolysis, and biodisposition. 

Enzymatic hydrolysis of the beta-lactam ring results in loss of antibacterial activity. The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative organisms is thus a major mechanism of bacterial resistance. Inhibitors of these bacterial enzymes (eg, clavulanic acid, sulbactam, tazobactam) are sometimes used in combination with peni-... 

Polymerization of benzylpenicillin has been described by several authors (Batchelor et al. 1967 Stewart 1967 a de Weck et al. 1968 Butcher and Stewart 1969, 1970 Dewdney et al. 1971 Smith et al. 1971 Smith and Marshall 1971 Bungaard and Larsen 1977). Polymerization probably involves hydrolysis of the beta-lactam ring to form penicilloic acid, followed by acylation of the exposed thiazolidine nitrogen by another intact penicillin molecule or a benzyl-penicillenic acid derivative (Stewart 1973 Smith and Marshall 1971 Schneider and de Weck, 1970) (Fig. 8) Such polymers have been isolated by Sephadex gel chromatography (Smith et al. 1971) or by high-pressure liquid chromatography (Bundgaard 1977 b). Polymers have been isolated also from other semisynthetic penicillins such as hetacillin and carbenicillin (Smith et al. 1971), methicillin and pheneticillin (Butcher and Stewart 1970). 

The beta-lactam antibiotics are anionic, unstable to hydrolysis, and act by inhibiting the synthesis of the bacterial cell wall. 

Theoretical study of the alkaline hydrolysis of a bicyclic aza-beta-lactam ... 

In this chapter we present the detailed setup of ligand-based NMR experiments and an NMR-based functional assay using a 30 kDa enzyme protein that makes bacteria resistant to a broad range of beta-lactam antibiotics. STD, c-STD, and STDD were used for fragment screening and an NMR-based functional assay that monitors the hydrolysis of ampicillin was used for functional validation of fragment hits with weak affinities/activities. 

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