Antibiotics, 3-lactam, the mechanisms

Antibiotics have a wide diversity of chemical stmctures and range ia molecular weight from neat 100 to over 13,000. Most of the antibiotics fall iato broad stmcture families. Because of the wide diversity and complexity of chemical stmctures, a chemical classification scheme for all antibiotics has been difficult. The most comprehensive scheme may be found ia reference 12. Another method of classifyiag antibiotics is by mechanism of action (5). However, the modes of action of many antibiotics are stiU unknown and some have mixed modes of action. Usually within a stmcture family, the general mechanism of action is the same. For example, of the 3-lactams having antibacterial activity, all appear to inhibit bacterial cell wall biosynthesis. 

Studies on the mechanism of action of /3-lactam antibiotics have shed considerable light on how these agents kill bacteria. They also help explain qualitative differences between various agents and why there is a correlation between the reactivity of the /3-lactam and antibacterial activity. However, it is also clear that reactivity is only one factor in determining how effectively a given /3-lactam antibiotic will inactivate bacterial enzymes (82BJ(203)223). 

A third resistance mechanism is akin to that described for the AGAC antibiotics and chloramphenicol, whereby changes in the outer membrane porins of Gram-negative bacteria reduce the penetration of /3-lactams resulting in low levels of resistance. 

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... 

Lactamases (EC 3.5.2.6) inactivate /3-lactam antibiotics by hydrolyzing the amide bond (Fig. 5.1, Pathway b). These enzymes are the most important ones in the bacterial defense against /3-lactam antibiotics [15]. On the basis of catalytic mechanism, /3-lactamases can be subdivided into two major groups, namely Zn2+-containing metalloproteins (class B), and active-serine enzymes, which are subdivided into classes A, C, and D based on their amino acid sequences (see Chapt. 2). The metallo-enzymes are produced by only a relatively small number of pathogenic strains, but represent a potential threat for the future. Indeed, they are able to hydrolyze efficiently carbape-nems, which generally escape the activity of the more common serine-/3-lac-tamases [16] [17]. At present, however, most of the resistance of bacteria to /3-lactam antibiotics is due to the activity of serine-/3-lactamases. These enzymes hydrolyze the /3-lactam moiety via an acyl-enzyme intermediate similar to that formed by transpeptidases. The difference in the catalytic pathways of the two enzymes is merely quantitative (Fig. 5.1, Pathways a and b). 

It is clinically important to understand the nature of the mechanism of resistance to an antibiotic drug. For example, the -lactam resistance of Streptococcus pneumoniae is due to the appearance of altered penicillinbinding proteins. Thus, the use of a combination of a 3-lactam and a penicillinase inhibitor, such as clavulanate, wUl not overcome streptococcal -lactam resistance, because the mechanism of resistance is not due to the production of a penicillinase. 

A number of antibiotics produced by fungi of the genus Cephalosporium have been identified. These antibiotics called cephalosporins contain, in common with the penicillins, a p-lactam ring. In addition to the numerous penicillins and cephalosporins in use, three other classes of p-lactam antibiotics are available for clinical use. These are the carbapenems, the carbacephems, and the monobactams. All 3-lactam antibiotics have the same bactericidal mechanism of action. They block a critical step in bacterial cell wall synthesis. 

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 newest classes of (3-lactam antibiotics are the car-bapenems and carbacephems. Their mechanism of action is the same as those of the other (3-lactam antibiotics. 

Cephalosporins, a common class in the )0-lactam family of antibiotics, are therapeutically important/advantageous for their broad antibacterial activity. Out of a total worldwide production of around 5x10 kg/annum, the /i-lactam group constitutes an amount of the order of 3 X 10 kg/annum. Penicillins and cephalosporins are the main constituents of commercially important /i-lactams and they are mainly produced by biosynthetic routes, the mechanism of which is now fairly well understood [ 1 ]. 

The mechanism of action of /3-lactam antibiotics has been the subject of several recent reviews (79MI51102, 79MI51103, 81MI51104, B-81MI51105, B-82MI51101). 

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... 

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