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Understanding antibiotic resistance
Understanding antibiotic resistance

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3 Case study: mechanism of ß-lactams

The β-lactam antibiotics target the bacterial cell wall (Figure 8) by inhibiting the enzymes responsible for cross-linking adjacent molecules in the peptidoglycan layer. The ß-lactam antibiotics bind to these enzymes, collectively known as penicillin-binding proteins (PBPs), and prevent them from forming cross-links. As the bacterial cell grows, the effect of the antibiotic is to progressively weaken the cell wall until the cell lyses as a result of osmotic damage.

A diagram of the structure and arrangement of peptidoglycan chains in the bacterial cell wall.
Figure 8 Structure and arrangement of peptidoglycan chains in the bacterial cell wall. Peptidoglycan molecules consist of a backbone of carbohydrate units with sets of amino-acid residues attached (yellow). They are cross-linked by bridges (red), providing structure and strength.

In Section 2 you learned that the activity of penicillins and cephalosporins resides in the ß-lactam ring. Activity 3 looks more closely at this.

Activity 3 Mechanism of ß-lactam antibiotics

Timing: Allow about 15 minutes

First, watch the short video below which describes the inherent instability of the ß-lactam ring structure which makes it highly reactive. The video refers to penicillin, but the same is true of the ß-lactam ring in cephalosporins and all other antibiotics of this class.

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Video 4 The inherent instability of the ß-lactam ring structure.
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Figure 9 shows what happens when a ß-lactam antibiotic, in this case penicillin, binds to an active PBP.

Reaction of penicillin with a PBP.
Figure 9 Reaction of penicillin with a PBP. The -NH2 side chain of the PBP reacts with the ß-lactam ring of penicillin to form a new side chain. This reaction releases the strain in the ß-lactam ring which remains open.

The reaction shown in Figure 9 results in a new PBP side chain which is much larger than the original -NH2 group and effectively deactivates the PBP. Can you suggest why?

Answer

The large side chain means that there is no longer sufficient space for the enzyme (PBP) to bind to its normal substrate during the peptidoglycan cross-linking process.

You will learn more about how disrupting the interaction between ß-lactam antibiotics and PBP contributes to antibiotic resistance mechanisms in Week 3. Next, however, you will see how antibiotics of the same class, and with the same mode of action, can have a different spectrum of activity and exert different effects.