3-Lactam antibiotics, the mechanisms of reactions

The mechanism of serine (3-lactamases is similar to that of a general serine hydrolase. Figure 8.14 illustrates the reaction of a serine (3-lac(amasc with another type of (3-lactam antibiotic, a cephalosporin. The active-site serine functions as an attacking nucleophile, forming a covalent bond between the serine side chain oxygen... 

Mechanisms, of proton transfer between oxygen and nitrogen acids and bases in aqueous solutions, 22, 113 Mechanisms, organic reaction, isotopes and, 2, 1 Mechanisms of reaction, in solution, entropies of activation and, 1, 1 Mechanisms of reaction, of /3-lactam antibiotics, 23, 165 Mechanisms of solvolytic reactions, medium effects on the rates and, 14, 10 Mechanistic analysis, perspectives in modern voltammeter basic concepts and, 32, 1 Mechanistic applications of the reactivity-selectivity principle, 14, 69 Mechanistic studies, heat capacities of activation and their use, 5, 121 Mechanistic studies on enzyme-catalyzed phosphoryl transfer, 40, 49 Medium effects on the rates and mechanisms of solvolytic reactions, 14, 1 Meisenheimer complexes, 7, 211... 

The incidence of nonallergic ampicillin eruptions is 40 to 100% in patients with concomitant Epstein-Barr virus (mononucleosis), cytomegalovirus, acute lymphocytic leukemia, lymphoma, or reticulosarcoma. Nonallergic penicillin-associated rashes are characteristically morbilliform (symmetrical, erythematous, confluent, maculopapular) eruptions on the extremities. The onset of typical nonallergic eruptions is more than 72 hours after (3-lactam exposure. The mechanism for the nonurticarial ampicillin rash is not known and is not related to IgE or type I hypersensitivity. Penicillin skin tests are not useful in the evaluation of nonurticarial ampicillin rashes. Patients with a history of nonurticarial ampicillin rashes may receive other (3-lactam antibiotics without greater risk of subsequent serious allergic reactions. 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

Non-IgE-antibody-mediated immunological reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products is thought to be the cause of the formation of antierythrocyte antibodies and the development of a positive Coombs test implicated in the development of immune hemolytic anemia (211). About 3% of patients receiving large doses of intravenous penicillin (10-20 million units/ day) will develop a positive direct Coombs test (212). However, only a small fraction of Coombs positive patients will develop frank hemolytic anemia (213). Antibody-coated erythrocytes are probably eliminated by the reticuloendothelial system (extravascular hemolysis) (214), or less often by complement-mediated intravascular erythrocyte destruction (215). Another mechanism implicates circulating immune complexes (anti-beta-lactam antibody/beta-lactam complexes), resulting in erythrocyte elimination by an innocent bystander mechanism (82). Similar mechanisms have been implicated in thrombocytopenia associated with beta-lactam antibiotics (216,217). 

Reactions of ketenes with imines open a useful route to (3-lactams [27]. The stereospecificity of these reactions has been extensively investigated given the practical importance of 3-lactam antibiotics [28]. The generally accepted mechanism of this cycloaddition is outlined below (Scheme 10.7). 

The utility of this reaction was illustrated by the conversion of (69) to the jS-lactam antibiotic ( + )-PS-5 (70) <93BMC2415>. The palladium(0)-catalyzed conversion of 2-dienylaziridines such as (71) to 3-pyrrolines (72) is believed to proceed by the same mechanism (Equation (34)) <85TL857>. 

An in situ method for the preparation of N-methyleneamines has been devised by Overman and Osawa for use in condensation reactions with enolates and organometallic reagents. These species, with the exception of very hindered N-methyleneamines, cannot be isolated in the condensed phase because they rapidly trimerize to hexahydro-l,3,5-triazines. In this in situ method, A -methyleneamines (230) are generated from N-(cyanomethyl)amines (228) by deprotonation with an equivalent of enolate to give an intermediate amide (229) which loses LiCN (equation 22). When two equivalents of enolate are present, addition to the N-methyleneamine occurs and 3-lactams (233) are obtained in 60-70% yield upon warming the reaction mixture to 25 C (Scheme 48 Table 26). Uncyclized 3-amino esters can be isolated if the reaction is quenched at lower temperature a possible cycloaddition mechanism is thus ruled out. It is not clear to what extent, if any, the reaction is limited to a,a-disubstituted enolates. N-Methyleneamines, like oxime ethers, are useful for the synthesis of 4-unsubstituted 3-lactams and should also have important applications in the synthesis of monobactam antibiotics. 

A variety of enzymatic mechanisms for antibiotic resistance are known. Hydrolysis of the lactam rings of /3-lactams, cephalosporins, and carbapenams destroys their ability to inhibit transpeptidases that cross-link peptidoglycan in bacterial cell walls. Modification of aminoglycoside antibiotics by acetylation, phosphorylation, or adenylation interferes with their ability to bind to the 16S subunit of the ribosome. Streptogramin activity can be destroyed by acetylation or by an elimination reaction that opens the lactone ring. The enzymes responsible for these detoxification reactions evolved in response to naturally occurring antibiotics, but are easily adapted to modify semisynthetic and completely synthetic antibiotics. For example, only a few point mutations are needed to enhance the ability of TEM /3-lactamases to hydrolyze third-generation cephalosporins such as cefotaxime and ceftazidime. ... 

In general these enzymes catalyze the hydrolytic opening of the p-lactam ring according to the reaction depicted in Fig. 11.26. The hydrolytic product, unlikely the intact P-lactam, is not able to interfere with bacterial cell wall synthesis, the key effect of the antibiotic [229]. The crystal structures of several metaUo-p-lacta-mases have shown that the active site can have one or two Zn(ll) ions (Znl and Zn2) then separated by 3.5 A [242-247]. In these structures Znl is tetrahedraUy coordinated to three His and one water molecule. When present, Zn2 is either penta-coordinated to Cys, His and Asp residues and two water molecules, or to two His, one Asp and two water molecules, in a trigonal bipyramid. In the structure where the active site is composed of a binuclear Zn center, a H20/0H bridges the two metals. As in other binuclear centers with bridging solvent molecules, its activation provides the OH nucleophile for the reaction [248]. It should be pointed out that not all P-lactam antibiotics bind to the active site in the same way so mechanisms may differ from molecule to molecule. 

Other important reactions of the [3-lactam antibiotics, such as attack by bacterial lactamases and reaction with penicillin-binding proteins (e.g. transpeptidase enzyme), proceed via an identical mechanism of nucleophilic attack on the C-7 carbon. 

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