2.1 Inhibitors of cell wall synthesis

As you saw in Activity 2, the cell wall is essential for normal functioning of the bacterial cell. Antibiotic inhibitors of cell wall synthesis block the production of peptidoglycan, the main component of the cell wall. Cross-linking between peptidoglycan chains forms a strong, mesh-like structure that gives the cell wall structure and rigidity, and protects the underlying cell membrane from osmotic damage when water moving into the cell by osmosis could cause it to burst, or lyse. Disruption of the peptidoglycan layer of the cell wall can therefore result in cell lysis (Figure 3).

Figure 3 Lysis of a bacterium with a defective cell wall. (a) Diagram showing the sequence of events that lead to lysis. (b) Light micrograph of S. aureus: a lysed cell on the left and an intact dividing cell on the right.

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Part (a) is a schematic diagram showing the sequence of events that lead to the osmotic lysis of a bacterium. Initially the cell wall and the cell membrane beneath it are intact. As water enters by osmosis, the cell wall becomes defective. Eventually the cell contents and surrounding membrane expand through the defective cell wall, the membrane then ruptures and the cell contents spill out; that is, the cell lyses. In the light micrograph in part (b), the intact near-spherical cell appears orange–yellow on the black background; while the lysed cell has collapsed and lost most of its contents and so has a shrivelled shape and appears mostly black.

Figure 3 Lysis of a bacterium with a defective cell wall. (a) Diagram showing the sequence of events that lead to lysis. (b) Light ...

Examples of cell wall synthesis inhibitors are the ß-lactam antibiotics. These include penicillin and its derivatives, and the cephalosporins. All ß-lactam antibiotics contain a core chemical structure called a ß-lactam ring (Figure 4) which determines the mode of action of this class of antibiotics.

Figure 4 Core ring structures of two types of β-lactam antibiotics. The β-lactam ring is shaded pink in each case.

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This figure shows the core ring structures of penicillins (top) and cephalosporins (bottom). They both contain a ring that is joined to the common beta-lactam ring (shaded in pink), but the structure of this ring differs between the two classes: the penicillins have a sulphur (S)-containing 5-membered ring with no double bonds; the cephalosporins have a sulphur (S)-containing 6-membered ring with one double bond.

Figure 4 Core ring structures of two types of β-lactam antibiotics. The β-lactam ring is shaded pink in each case.

The ß-lactam antibiotics interfere with the formation of the peptidoglycan cross-links, thereby weakening the cell wall. You will learn more about the precise mechanism in this week’s case study (Section 3). For now, you can see the effect of the disrupted cell wall on bacterial growth in Video 3.

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Transcript: Video 3 A ß-lactam antibiotic in action.

INSTRUCTOR:

This is cephalosporin C, the first compound in one of the most important classes of beta-lactams-- the cephalosporins. It occurs in nature and was originally isolated from a fungus found growing in a sewage outlet in Sardinia in 1947. It's the lead compound from which a whole family of antibiotics has been made, but it isn't itself a particularly powerful antibiotic. Why? It all hinges in the way that antibiotics work. What they do is disrupt the process of cell wall biosynthesis. In a growing colony, this process is taking place all the time, both to maintain the existing cell wall and to make new wall as the bacteria divide.

When an antibiotic is added to a colony, this inhibitory action has two effects. Firstly, the bacteria are prevented from successfully dividing, so they start to form long, spaghetti-like strings. The other effect arises from the fact that the existing cell walls routinely break down and are in constant need of repair. As the process of repair is prevented, small flaws appear, large enough to allow water to start moving into the cell due to the high internal osmotic pressure. As a result, the cells start to swell and eventually burst, a process called lysis.

End transcript: Video 3 A ß-lactam antibiotic in action.

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Video 3 A ß-lactam antibiotic in action.