![]() It is a narrow-spectrum antibacterial with activity only against gram-negative bacteria. The only monobactam used clinically is aztreonam. The carbapenems and monobactams also have a β-lactam ring as part of their core structure, and they inhibit the transpeptidase activity of penicillin-binding proteins. A new fifth-generation cephalosporin has been developed that is active against methicillin-resistant Staphylococcus aureus (MRSA). The family of semisynthetic cephalosporins is much larger than the penicillins, and these drugs have been classified into generations based primarily on their spectrum of activity, increasing in spectrum from the narrow-spectrum, first-generation cephalosporins to the broad-spectrum, fourth-generation cephalosporins. Another important structural difference is that cephalosporin C possesses two R groups, compared with just one R group for penicillin, and this provides for greater diversity in chemical alterations and development of semisynthetic cephalosporins. The drug cephalosporin C was originally isolated from the fungus Cephalosporium acremonium in the 1950s and has a similar spectrum of activity to that of penicillin against gram-positive bacteria but is active against more gram-negative bacteria than penicillin. This chemical difference provides cephalosporins with an increased resistance to enzymatic inactivation by β-lactamases. However, the β-lactam ring of cephalosporins is fused to a six-member ring, rather than the five-member ring found in penicillins. Similar to the penicillins, cephalosporins contain a β-lactam ring ( Figure 14.10) and block the transpeptidase activity of penicillin-binding proteins. Changing the R group of penicillin G to the more bulky dimethoxyphenyl group provided protection of the β-lactam ring from enzymatic destruction by penicillinases, giving us the first penicillinase-resistant penicillin. Methicillin is a semisynthetic penicillin that was developed to address the spread of enzymes ( penicillinases) that were inactivating the other penicillins. Furthermore, the addition of a hydroxyl group (-OH) to amoxicillin increased acid stability, which allows for improved oral absorption. Adding an amino group (-NH 2) to penicillin G created the aminopenicillins (i.e., ampicillin and amoxicillin) that have increased spectrum of activity against more gram-negative pathogens. Figure 14.10 summarizes the semisynthetic development of some of the penicillins. Penicillin G and penicillin V are natural antibiotics from fungi and are primarily active against gram-positive bacterial pathogens, and a few gram-negative bacterial pathogens such as Pasteurella multocida. Although the β-lactam ring must remain unchanged for these drugs to retain their antibacterial activity, strategic chemical changes to the R groups have allowed for development of a wide variety of semisynthetic β-lactam drugs with increased potency, expanded spectrum of activity, and longer half-lives for better dosing, among other characteristics. They are able to block this process because the β-lactam structure is similar to the structure of the peptidoglycan subunit component that is recognized by the crosslinking transpeptidase enzyme, also known as a penicillin-binding protein (PBP). The β-lactam antibacterials block the crosslinking of peptide chains during the biosynthesis of new peptidoglycan in the bacterial cell wall. This group of compounds includes the penicillins, cephalosporins, monobactams, and carbapenems, and is characterized by the presence of a β-lactam ring found within the central structure of the drug molecule ( Figure 14.10). Penicillin, the first antibiotic discovered, is one of several antibacterials within a class called β-lactams. Because human cells do not make peptidoglycan, this mode of action is an excellent example of selective toxicity. Therefore, antibacterials that target cell wall biosynthesis are bactericidal in their action. Several different classes of antibacterials block steps in the biosynthesis of peptidoglycan, making cells more susceptible to osmotic lysis ( Table 14.2). Table 14.1 Inhibitors of Cell Wall Biosynthesis ![]()
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