1.2 Destroying or modifying the antibiotic molecule

The second mechanism of antibiotic resistance you will look at is the destruction or modification of the antibiotic by bacterial enzymes. Probably the most well studied example of enzymes that destroy antibiotics are the β-lactamases.

As you may recall from Week 2, β-lactamases deactivate the β-lactam ring of β-lactam antibiotics, preventing them from binding to their target (Figure 3).

Figure 3 Inactivation of a β-lactam antibiotic by β-lactamase.

Show description|Hide description

This figure is a chemical equation showing the ring-opening reaction. The bond in the beta-lactam ring (highlighted in pink) that is broken is the amide linkage between the carbonyl (C=O) carbon and the nitrogen to which it is attached. This N atom is shared between the beta-lactam ring and the adjacent ring. The result of the hydrolysis reaction is a free carboxyl (COOH) group and an NH group in the remaining ring.

Figure 3 Inactivation of a β-lactam antibiotic by β-lactamase.

The β-lactamases can deactivate almost all of the β-lactam antibiotics currently in therapeutic use. As you will see in the case study at the end of this week, this includes cephalosporins. Consequently, their presence significantly reduces the available treatment options for infections caused by bacteria expressing β-lactamase. One successful strategy for treating these infections is to combine antibiotic treatment with a β-lactamase inhibitor.

Other antibiotic-modifying enzymes do not destroy or target the core chemical structure that confers antibacterial activity. Instead they modify the antibiotic’s structure by adding chemical groups to prevent it from binding to its target. One group of antibiotics that are particularly susceptible to modification are the aminoglycoside antibiotics which include streptomycin (Figure 4).

Figure 4 Structure of streptomycin. An exposed hydroxyl (-OH) group that can be modified by aminoglycoside-modifying enzymes is highlighted in green (in the figure the hydroxyl group is shown as -HO – this is the same as -OH).

Show description|Hide description

This figure shows the structure of streptomycin, an aminoglycoside. It has three rings including both a 5-membered and a 6-membered sugar ring. All three rings have hydroxyl and amino groups attached; and one of the two OH substituents (highlighted in green) on the 6-membered sugar ring is a target site for inactivating enzymes.

Figure 4 Structure of streptomycin. An exposed hydroxyl (-OH) group that can be modified by aminoglycoside-modifying enzymes is ...

Aminoglycoside-modifying enzymes add bulky chemical groups to the exposed hydroxyl (-OH) and amino (-NH₂) groups of the antibiotic, which prevent it from binding to its target.