Benzylpenicillin penicillin 3-lactam antibiotics

Fig. 5.20. Modes of coordination of transition metal ions with /3-lactam antibiotics. Complex A In penicillins, the metal ion coordinates with the carboxylate group and the /3-lactam N-atom. This complex stabilizes the tetrahedral intermediate and facilitates the attack of HO-ions from the bulk solution. Complex B In benzylpenicillin Cu11 binds to the deprotonated N-atom of the amide side chain. The hydrolysis involves an intramolecular attack by a Cu-coordinated HO- species on the carbonyl group. Complex C In cephalosporins, coordination of the metal ion is by the carbonyl O-atom and the carboxylate group. Because the transition state is less stabilized than in A, the acceleration factor of metal ions for the hydrolysis of cephalosporins is lower than for penicillins. Complex D /3-Lactams with a basic side chain bind the metal ion to the carbonyl and the amino group in their side chain. This binding mode does not stabilize the tetrahedral transition complex and, therefore, does not affect the rate of... 

Penicillin and cephalosporin antibiotics are usually classed as P-lactam antibiotics, since their common feature is a lactam function in a four-membered ring, typically fused to another ring system. This second ring takes in the P-lactam nitrogen atom and also contains sulfur. In the case of penicillins, e.g. benzylpenicillin, the second ring is a thiazolidine, and in the cephalosporins, e.g. cephalosporin C, this ring is a dihydrothiazine. What is not readily apparent from these structures is that they are both modified tripeptides and their biosyntheses share a common tripeptide precursor. 

Since the first X-ray structure determination of benzylpenicillin potassium 42 (a penam) in 1949, the structures of a large number of -lactam antibiotics have been reported . Table 2 shows the limiting values of the -lactam ring dimensions in a range of penicillin derivatives . More recent X-ray studies on the penicillin and cephalosporin families of antibiotics have been summarized. 

Canadian data have partly confirmed these findings (169). Benzylpenicillin derivatives and semisynthetic penicillins were applied to 112 patients with a history of an allergic reaction to penicillins. The tests were positive in 21 patients (19%), of whom 10 reacted against the semisynthetic penicillin reagents only. Reports of subjects allergic to flucloxacillin (186), cloxacillin (187), and cefa-droxil (188), but not penicillin, lend further support to the concept of side chain-specific allergic reactions (see the monograph on beta-lactam antibiotics). 

Benzylpenicillin is produced as various salts according to its intended use, whether as an input to semisynthetic (3-lactam antibiotics manufacture or for clinical use in its own right. The treatment of the crude penicillin extract varies according to the objective but involves formation of an appropriate... 

Binding of (3-lactam antibiotics to PBP-1A and PBP-1 B (transpeptidase) of Escherichia coii leads to cell lysis to PBP-2 (transpeptidase) leads to oval cells deficient in rigidity and to inhibition of cell division to PBP-3 (transpeptidase) leads to abnormally long, filamentous shapes by failure to produce a septum and to PBP-4 through PBP-6 (carboxypeptidases) leads to no lethal effects. Approximately 8% of a dose of benzylpenicillin binds to PCP-1, 0.7% to PCP-2, 2% to PBP-3, 4% to PBP-4, 65% to PBP-5, and 21% to PBP-6. Thus, the majority of the penicillin dose bonds to PBPs for which the function remains obscure. Binding to PBP-1 is lethal. Other (3-lactam antibiotics display different binding patterns. Amoxicillin and the cephalosporins bind more avidly to PBP-1, methicillin and cefotaxime to PBP-2, and mezlocillin and cefuroxime to PBP-3. All these drugs are lethal to susceptible bacteria. 

Lactamases are bacterial enzymes, some of which play a crucial role in the resistance of pathogens to /3-lactam antibiotics. They are grouped into four classes (A, B, C, and Classes A, C, and D are serine enzymes using serine as a nucleophile, which are excluded in this text. Class B /3-lactamases include mononuclear zinc(II)-/3-lactamases and dinuclear zinc(II)-/3-lactamases. " A Zn -containing /3-lactamase II hydrolyzes the /3-lactam ring of a variety of penicillins (e.g., benzylpenicillin) and cephalosporins. At pH 7 and 30 ""C, the half-life of benzylpenicillin bound to /3-lactamase II is ca. 0.5 ms. The first structure of the... 

It is important to understand the mechanism of the cleavage of the (3-lactam ring catalyzed by 3-lactamase involving a zinc atom as an active site, because the zinc-containing enzyme is a factor in bacterial resistance to the 0-lactam antibiotics such as penicillin, cephalosporin, and so on. The first functional model for (3-lactamase was reported by Kimura and coworkers. " They demonstrated that the zinc complex involving 1,4,7,10-tetra-azacyclododecane ([12]aneN4) forms the [Zn—OH]" species under neutral conditions, and it accelerated the hydrolysis of benzylpenicillin in aqueous solution. In contrast, the native P-lactamase has two zinc atoms in the active site. From the three-dimensional structure infor-... 

The penicillins and cephalosporins, collectively known as beta-lactam antibiotics, are among the most widely used and valuable antibiotics currently available. Ben-zylpenicilhn (penicillin G) and phenoxymethylpenicillin (penicillin V) are derived from Penicillium molds by fermentation, while half-synthetic penicillins are derived by chemical modification of the penicillin nucleus, 6-aminopenicillanic acid (6-APA), itself obtained either by splitting the side chain from benzylpenicillin through an enzymatic process or via a chemical deacylation reaction. 

Penicillin (or benzylpenicillin) (32a) (R = CH2Ph) was first dicovered by Sir Alexander Fleming in 1929, who isolated the antibiotic from the fungal strain Penicillium notatum (see Introduction, p. 4). Penicillin is valuable to combat bacterial infections in man and animals. It was first manufactured commercially in 1945 and the first semisynthetic penicillins were introduced in 1954. The penicillins (32) have a common structural feature, namely a p-lactam ring fused to the... 

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