Beta-lactam ring

Boyd DB, Hermann RB, Presti DE, Marsh MM. Electronic structures of cephalosporins and penicillins. 4. Modeling acylation by the beta-lactam ring. / Med Chem 1975 18 408-17. 

Y. Okamoto, K. Kiriyama, Y. Namiki, J. Matsushita, M. Fujioka, T. Yasuda, Degradation Kinetics and Isomerization of Cefdinir, a New Oral Cephalosporin, in Aqueous Solution. 2. Hydrolytic Degradation Pathway and Mechanism for beta-Lactam Ring Opened Lactones , J. Pharm. Sci. 1996, 85, 984-989. 

This antibiotic class has the highest number of antibiotics on the market. All P lactam antibiotics have a basic fl-lactam ring structure and other classes are categorized based on the structure of the ring adjacent to the beta-lactam ring (Fig. 3). The majority of the fl-lactams derived from natural products and approved for human use are listed in Table 2. 

Finally, the most important mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamase by the bacteria. Beta-lactamases break the C-N bond in the beta-lactam ring of antibiotics. Since its existence is absolutely necessary for reacting with PBP, a break in the beta-lactam ring leads to a loss of antibacterial activity. 

The cephalosporin nucleus is synthesized with a beta-lactam ring attached to a six-membered dihydrothiazine ring. Unlike the penicillin nucleus, the cephalosporin nucleus is much more resistant to beta-lactamase. Moreover, it has large areas for possible modifications. Modifications Rj in the acyl side chain alter the antibacterial activity, while modifications of R2 are associated with changes in the pharmacokinetics and metabolic parameters of the drug. 

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. 

It is believed that the methyl group at position 4 increases the stability of the beta-lactam ring with respect to most beta-lactamases, and at the same time it does not induce formation of beta-lactamase as cephalosporins and imipenems do. 

Some penicillins cannot be given orally as their beta-lactam ring is hydrolyzed and inactivated in the stomach by gastric acid. In general intramuscular injections are painful and therefore not advised. The pharmacokinetic behavior of penicillins is further characterized by short elimination half-lives. Renal elimination is prominent. 

Penicillin was originally extracted from the mould Penicillium notatum but now it is extracted from its related mould Penicillium chrysogenum due to its high yield. Penicillin consists of thiazolidine ring fused with a beta lactam ring which is essential for its antibacterial activity. These two rings forms a nucleus named as 6-aminopenicillanic acid. 

Cephalosporins are important bactericidal broad spectrum (3-lactam antibiotics used for the treatment of septicaemia, pneumonia, meningitis, urinary tract infections, peritonitis and biliary tract infections. They are obtained from fungus Cephalosporium acremonium and are chemically related to penicillin. It consists of beta lactam ring fused to a dihydrothiazine ring. 

Plasmids are autonomously replicating pieces of extrachromosomal DNA present in bacteria. They are encoded with subtle, yet vital, changes for the synthesis of important cellular proteins. Because they are relatively large, they can contain information pertaining to several genes. One of these genes codes for beta-lactamase, an enzyme that can hydrolyze the four-member heterocyclic beta-lactam ring present in penicillins and cephalosporins. 

In reality, the situation is more subde because very often the synthesis of direct analogues is justified by a desire to improve the existing drug. Thus, for penicillins the chemical structure that surrounds the beta-lactam ring is still being modified. Current antibiotics that have been derived from this research (e.g., the cephalosporins) are more selective, more active on resistant strains, and can be administered by the oral route. They are as different from the parent molecule as a recent car compared to a 40-year-old model In other words, innovation can result from the sum of a great number of stepwise improvements, as well as from a major breakthrough. 

The beta-lactam antibiotics still comprise roughly half of the antibiotic market worldwide. The common structure that defines the whole family of beta-lactam antibiotics is the four-membered, highly reactive beta-lactam ring, which is essential for antimicrobial activity (1). The following simplif)dng classification is practical ... 

Despite their chemical diversity, their adverse effects profiles share various common aspects. There are several reasons why beta-lactam antibiotics belonging to different classes can cause comparable reactions. Besides the beta-lactam ring, other structural similarities (for example side chains) or antimicrobial activity can be relevant. However, the incidence of a given reaction, and in particular instances also the severity, varies among beta-lactam classes. 

Imipenem, which is related to meropenem, has also been reported to cause toxic epidermal necrolysis (34). The authors stated that to the best of their knowledge, this was the first report of a possible cross-reaction between two classes of antibiotics in causing toxic epidermal necrolysis. The time between first administration and the occurrence of epidermal necrolysis is considerably shorter in recurrence or provocation testing (35,36). They also claimed that it is likely that the beta-lactam ring is responsible for this hypersensitivity reaction, citing the evidence that the patient had been given amoxicillin 15 days before the cephalosporin, and that could have served as the sensitizing event. They did not discuss whether aztreonam, a monobactam, also could have caused a cross-reaction however, it has been involved in two cases of fatal toxic epidermal necrolysis (37). 

In the monobactams there is no second ring fused to the beta-lactam ring. However, the highly active compounds of this group do, as a rule, contain the aminothiazole side chain, known to be associated with good antimicrobial activity and beta-lactamase stability in cephalosporins (1). Aztreonam, marketed in 1984, was the first monobactam. 

The beta-lactam antibiotics are commonly used because of their safety, efficacy, relatively low cost and the variety of dosage forms available. Both penicillins and cephalosporins have a four-membered beta-lactam ring that is responsible for the instability of these compounds. The penicillins are also relatively insoluble they are prepared as various salts by the substitution of the hydroxyl group or the hydrogen of the carboxyl group with sodium, potassium, benzathine or procaine. 

Penicillins and cephalosporins Production of beta-lactamases, which cleave the beta-lactam ring structure change in penicillin-binding proteins change in porins... 

Identical to penicillins in terms of mechanism of action (bind to PBPs) are bactericidal and require the intact beta-lactam ring structure for activity. Substituents at R1 group — spectrum variations, substituents at R2 group —> kinetic variations (see Beta Lactam Antibiotics figure). 

Robert Robinson refused to accept the beta-lactam ring, suggesting that is the result when penicillin is in the solid form. You simply do not know what it is when the penicillin is in solution. ... 

The three-dimensional structure of the beta-lactam portion of both penicillins and cephalosporins is sufficiently similar to that of D-alanine-D-alanine (see Fig. 2.4), that the transpeptidase enzyme acts upon the drugs instead of the bacterial polypeptide chain. The enzyme becomes covalently attached to the antibiotic and is then unable to carry out its normal functions such that new cell wall material cannot be produced and the dividing bacterium cannot survive. Unfortunately, the penicillinases and cephalosporinases (now known collectively as beta-lactamases) that have evolved to meet the threat posed by the antibiotics act upon the drugs to destroy their beta-lactam rings so that they can no longer inactivate the transpeptidase enzymes. 

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