LACTAM

A lactam (the noun is a portmanteau of the words lactone + amide) is a cyclic amide. Prefixes indicate how many carbon atoms (apart from the carbonyl moiety) are present in the ring: β-lactam (2 carbon atoms outside the carbonyl, 4 ring atoms in total), γ-lactam (3 and 5 total), δ-lactam (4 and 6 total). Beta β, gamma γ and delta δ are the second, third and fourth letters in the alphabetical order of the Greek alphabet, respectively.

 

Synthesis

General synthetic methods exist for the organic synthesis of lactams.

• Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.
• Lactams form from cyclic ketones and hydrazoic acid in the Schmidt reaction.
• Lactams form from cyclisation of amino acids.
• Lactams form from intramolecular attack of linear acyl derivatives from the nucleophilic abstraction reaction.
• In iodolactamization an iminium ion reacts with an halonium ion formed in situ by reaction of an alkene with iodine.
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• Lactams form by copper catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction
• Diels-Alder reaction between cyclopentadiene and chlorosulfonyl isocyanate (CSI) can be utilized to obtain both β- as well as γ-lactam. At lower temp (−78 °C) β-lactam is the preferred product. At optimum temperatures, a highly useful γ-lactam known as Vince Lactam is obtained.

• A cyclic amide formed from aminocarboxylic acids by elimination of water; lactams are isomeric with lactims, which are enol forms of lactams.
  • β-l. antibiotics - including penicillin, cephalosporins, carbapenems and penems. See also the β-lactam ring (below).
  • β-l. ring - an integral part of the formula β-lactam antibiotics. Disruption from the ring by β-lactamases produced by some bacteria, Escherichia coli, for example, Bacillus anthracis, destroys the antimicrobial activity of compounds

 

Beta-lactam antibiotics

Beta-lactam antibiotics are a class of antibiotics that have a common structural component in the form of beta-lactam ring and is commonly used to treat bacterial infections. There are approximately ± 56 kinds antibotik beta-lactam antimicrobials that have antivitas on the beta-laktamnya cincing and if the ring is cut by microorganisms, there will be resistance to these antibiotics

The types of beta-lactam antibiotics

Beta-lactam antibiotics is divided into four main groups, namely penicillin, cephalosporin, carbapenem, and monobactam

a.     penicillin

Based on the spectrum antimikrobialnya activity, penicillin is divided into 4 groups, namely penicillin early (earlier), penicillin spektruk broad, anti-staphylococcal penicillins, and anti-pseudomonal penicillin (expanded spectrum). Early penicillin is actively able to fight bacteria that are sensitive, such as beta-hemolytic Streptococcus group, alpha-hemolytic Streptococcus in combination with an aminoglycoside), pneumococcus, meningococcus, and Clostridium groups other than C. difficile. Examples of previous penicillin is penicillin G and penicillin V [1]. Broad-spectrum penicillins have the ability to fight and the enteric bacteria more easily absorbed by the gram-negative bacteria but is still susceptible to the degradation of beta-lactamase, such as ampicillin, amoxicillin, mesilinam, bacampicillin, etc. Anti-staphylococcal penicillin was developed in the 1950s to cope with S. aureus that produce beta-lactamase and has the advantage of resistance to beta-lactamase activity . Examples of this group are methicillin and cloxacillin . Anti-pseudomonal penicillin made ​​to overcome the bacterial infection gram negative bacilli, including Pseudomonas aeruginosa, an example of this group are penicillin carbenicillin, ticarcillin, Azlocillin, and piperacillin.
cephalosporin
Antibioik divided into 3-generation cephalosporins, cephalothin and the first is that cephaloridine is not widely used. The second generation (among others: cefuroxime, cefaclor, cefadroxil, cefoxitin, etc..) Is widely used to address severe infections and some of which have activity against anaerobic bacteria . The third generation of cephalosporins (among them: ceftazidime, cefotetan, latamoxef, cefotetan, etc..) Made in the 1980s to cope with severe systemic infections due to gram-negative bacilli.

b. Sefalosporin

Antibioik divided into 3-generation cephalosporins, cephalothin and the first is that cephaloridine is not widely used. The second generation (among others: cefuroxime, cefaclor, cefadroxil, cefoxitin, etc..) Is widely used to address severe infections and some of which have activity against anaerobic bacteria . The third generation of cephalosporins (among them: ceftazidime, cefotetan, latamoxef, cefotetan, etc..) Made in the 1980s to cope with severe systemic infections due to gram-negative bacilli.

c. Carbapenem

There is only one class of carbapenem antibiotic agents that are used for clinical care, namely imipenem has excellent antibacterial ability against gram-negative bacilli (including P. aeruginosa, Staphylococcus, and Bacteroides). The use of imipenem must be combined with specific enzyme inhibitors to protect it from degragasi of liver enzymes in the body

d. Monobactam

This group has the structure of beta-lactam ring is not bound to the second ring in the molecule. One of this class of antibiotics commonly used is the aztreonam is active against many gram-negative bacteria, including P. aeruginosa

Mechanism of action

Beta-lactamase antibiotics work by killing bacteria menginhibisi cell wall synthesis. In the process of cell wall formation, a reaction catalyzed by the enzyme transpeptidasi transpeptidase and produce a bond between two peptide chains cross-glucan . Transpeptidase enzyme which is located on the cytoplasmic membrane of bacteria can also bind to beta-lactam antibiotics that cause the enzyme is not able to catalyze the reaction of the cell wall transpeptidasi although still continue to be formed. Cell wall is formed has no crosslinking and peptidoglycan formed is not perfect so much weak and easily degraded. In normal conditions, the difference in osmotic pressure within cells and gram-negative bacteria in the environment will make the occurrence of cell lysis. In addition, the complex protein transpeptidase and beta-lactam antibiotics will stimulate autolisin compounds that can mendigesti the bacterial cell wall. Thus, the loss of bacterial cell walls or through lysis will die.

Mechanisms of Resistance

Degradation mechanisms of beta-lactam antibiotics by the enzyme beta-lactamase.
Some bacteria are known to have resistance to beta-lactam antibiotics, one of which is the class of methicillin-resistant S. aureus (methicillin resistant Staphylococcus aureus / MRSA) . Bacteria that are resistant to beta-lactam antibiotics has three mechanisms of resistance, the destruction of the beta-lactamase antibiotics, reduce the penetration of antibiotic to bind to the protein transpepidase, and lower binding affinity of these binding proteins with antibiotic compounds . Some bacteria such as Haemophilus influenzae, Staphylococcus group, and most of the rod-shaped enteric bacteria have beta-lactamase enzymes that break down beta-lactam ring in antibiotics and makes it inactive . In detail, the mechanisms that occur beginning with the termination of the CN bond in the ring beta-lactam antibiotics and the resulting protein can not bind to transpeptdase resulting in loss of ability to menginhibisi formation of bacterial cell wall . Some studies suggest that in addition found naturally on gram positive and negative bacteria, the gene encoding the enzyme beta-lactamase was also found on the plasmid and the transposon so that it can be transferred between species of bacteria . This causes the resistance ability of the beta-lactam antibiotics would be able to spread rapidly . Diffusion of beta-lactam antibiotics into bacterial cells occurs through the mediation of transmembrane proteins called porine and diffusion capacity is influenced by size, charge, and the hydrophilic nature of the antibiotic.

Overcoming beta-lactam antibiotic resistance

To overcome the degradation of beta-lactam cincing, some beta-lactam antibiotics combined with the enzyme inhibitor compounds such as beta-lactamase clavulanat acid, tazobactam, or sulbactam. One of the beta-lactam antibiotic-resistant beta-lactamase is augmentin, Amoxycillin and clavulanic acid combination. Augmentin has been proven to successfully overcome the bacterial infection in the urinary tract and skin. Yng clavulanic acid is produced from the fermentation of Streptomyces clavuligerus has the ability to inhibit the enzyme beta-lactamase active, causing the enzyme to be inactive . Some types of beta-lactam antibiotics (eg, nafcillin) also have properties resistant to beta-lactamase because it has a side chain with a specific location .