Figure 21.4 The ß-Lactam Ring of Penicillins and Cephalosporins The core chemical structure of (a) a penicillin (b) a cephalosporin.The ß-lactam rings are marked by an orange circle.The R groups vary among different penicillins and cephalosporins.
properties such as acid stability, spectrum of activity, and halflife can be modified by chemically altering their structure.
The enzymes inhibited by b-lactam drugs mediate the formation of the peptide bridges between adjacent strands of peptidoglycan. They are called penicillin-binding proteins (PBPs), reflecting the fact that they bind penicillin and were initially discovered during experiments to study the effects of penicillin. Unfortunately, the name causes some confusion because it seems to imply that the natural biological function of the enzymes is to bind penicillin, when in fact their function is associated with peptidoglycan biosynthesis. In addition, the PBPs may bind any of a number of b-lactam drugs, not just the penicillins.
The b-lactam ring of the penicillins and other similar drugs bears structural similarity to the normal substrate of the PBPs. By mimicking that substrate, the b-lactam drugs are bound by PBPs and thus competitively inhibit their enzymatic activity. This causes a disruption in cell wall biosynthesis, leading to a series of events that ultimately causes the cells to lyse (figure 21.5). Because cell walls are only synthesized in actively multiplying cells, b-lactam drugs are only effective against growing bacteria. ■ competitive enzyme inhibition, p. 141
The different b-lactam drugs vary in their spectrum of activity. Some are more active against Gram-positive bacteria, whereas others are more active against Gram-negative organisms. One reason for this difference arises from the architecture of the cell wall. The peptidoglycan layer of Gram-positive organisms directly contacts the outside environment, making it readily accessible to drugs. In contrast, the outer membrane of Gram-negative bacteria excludes many antimicrobials, making many of these organisms innately resistant to many medications, including certain b-lactam drugs. Another difference is the affinity of an organism's penicillin-binding proteins for a particular b-lactam drug. The PBPs of Gram-positive bacteria differ somewhat from those of Gramnegative bacteria, and the PBPs of obligate anaerobes differ from those of aerobes. Differences in affinity can even exist among related organisms such as Gram-positive cocci.
Some bacteria can resist the effects of certain b-lactam drugs by synthesizing an enzyme called a b-lactamase that breaks
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