Introduction to Molecular Biology: From Cells to Atoms - Anthony Rees, Michael Sternberg 2002

Cells and molecules at work
How antibiotics work

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Fig. 42.1.

Antibiotics are chemical substances produced primarily by microorganisms that exert a direct and selective inhibitory effect on living Cells. The research of Paul Ehrlich in the late 19th century led to the discovery of chemical Dyes and Other Compounds capable of selectively targeting trypanosomes, spirochetes, and other parasites. Although Ehrlich's work was met with skepticism by his contemporaries, the discovery of penicillin by Fleming in 1928 and sulfonamides by Domagk in 1935 revived interest in antibiotics, and numerous new antibiotic substances were soon discovered. The term "antibiotics" generally refers to substances with antibacterial activity, although many antiviral and antitumor drugs are also antibiotics. Antibiotics can be broadly classified into two categories depending on whether they inhibit the growth of bacterial or Eukaryotic cells. Antibacterial antibiotics disrupt specific metabolic processes, leading either to the arrest of Cell growth (bacteriostatic action) or to cell death (bactericidal action). Table 42.1 lists Examples of some well-known antibiotics; all of these are produced by Fungi and actinomycetes. As the table shows, A wide variety of bacterial cell Functions can be blocked by antibiotics.

Table 42.1

Fig. 42.2.

The choice of specific antibiotics for clinical use depends on bacterial susceptibility and potential side effects. Antibiotics that target exclusively bacterial functions are obviously more suitable for clinical purposes than those affecting both prokaryotic and eukaryotic cells. For example, the widespread use of penicillin in treating bacterial infections is due to its specific action on the Prokaryotic Cell wall. Tetracycline is frequently used as an alternative; although it blocks protein synthesis—a metabolic process seemingly common to all cell types—it is actually highly specific for prokaryotic ribosomes (Ch. 24). We will now examine the MECHANISM OF ACTION of penicillin, while the Action of Certain antitumor drugs will be discussed in the next chapter.

PENICILLIN is a natural compound produced by the mold fungus Penicillium notatum. The penicillin molecule contains two fused rings: a thiazolidine ring and a β-lactam ring. The R group may vary. Structurally, penicillin is a cyclic dipeptide composed of L-Cysteine and D-valine (Ch. 6) attached to An acyl group (RCO—). The CO—N bond in the lactam ring is strained (due to its four-membered Structure) and is therefore easily hydrolyzed. The instability of this bond was one of the reasons why Fleming failed to establish the clinical use of penicillin, even though the antibiotic was effective in bacterial cultures. The most satisfactory of the originally obtained penicillins proved to be benzylpenicillin (penicillin G), in which R is a benzyl group. The first clues to the possible mechanism of action of penicillin emerged in 1957, when Lederberg discovered that penicillin-sensitive Bacteria could grow in its presence if they were in the form of protoplasts, i.e., devoid of a cell wall. Later, in 1965, Park and Strominger demonstrated that penicillin interferes with cross-linking during The final stage of Bacterial cell wall synthesis. At this stage, a peptide bond is formed between the amino group of the peptide bridge and the penultimate tetrapeptide residue (see Figs. 42.1 and 42.2) via D-ala (transpeptidation reaction).

Transpeptidation is catalyzed by the enzyme glycopeptide transpeptidase (transacylase). In The First stage of cross-linking, this enzyme must bind two D-Alanine residues located at the terminus of the pentapeptide (see Fig. 42.2; a hypothetical model of the enzyme-substrate complex is shown in Fig. 42.1). Then, by removing the terminal D-ala, the enzyme forms an acyl-intermediate with the penultimate D-ala, and finally the amino group of the bridging chain attacks the acyl-enzyme, resulting in cross-link formation and enzyme release. Penicillin inhibits this reaction because it structurally mimics the D-alanyl-D-alanine group and can occupy its designated site in the enzyme's active center (see Fig. 42.1). However, the effect is apparently not limited to the mere binding of penicillin to the enzyme: the latter likely attacks the β-lactam ring, leading to The formation of an acyl-enzyme that is incapable of deacylation (Fig. 42.3), thereby resulting in irreversible Enzyme Inhibition. Resistance to penicillin in certain bacterial species, such as many staphylococci, is due to the presence of the enzyme β-lactamase (penicillinase). This enzyme, which has a Molecular Weight of approximately 30,000, inactivates penicillin by cleaving its β-lactam ring.

Fig. 42.3.