β-lactam antibiotics are some of the most important weapons in the clinical fight against bacterial infection. Alexander Fleming's 1928 discovery, Penicillin, is a classic example of a β-lactam antibiotic.
R - C = O
N - H
H - C - C = O
H - C - N
H2C - C - H
O = C - OH
The general structure of penicillins
H - C - C = O
H - C - N
β-lactam ring structure
What do β-lactam antibiotics do?
β-lactam antibiotics act by inhibiting the action of bacterial transpeptidases, these enzymes catalyse the final cross linking step in the synthesis of the peptidoglycan layer of the bacterial cell wall. The cell wall of bacteria is constantly being degraded and synthesised so disrupting the cross linking is fatal to the bacterium.
How does β-lactam inhibit transpeptidase?
The β-lactam ring is structurally similar to the substrate of transpeptidase. It competes for active sites on the transpeptidase, and binds irreversibly. If enough is present then transpeptidase activity in the cell will be stopped completely, because the enzyme will not be able to bind to the substrate and therefore will not be able to catalyse the cross linking of the peptidoglycan layer. The cell literally falls apart.
Can β-lactams be inhibited?
The β-lactam ring is highly reactive, which leaves it susceptible to a number of degradative processes. It is sensitive to both OH- and H+ ions and so penicillins and other β-lactam drugs should be stored in a buffered solution. The sensitivity of the β-lactam ring to acid meant that the early penicillins couldn't be given orally, the acidity of the stomach would inactivate it.
In addition to chemical degradation a number of bacteria produce enzymes, known as penicillinases, which break down the β-lactam ring rendering it inactive against transpeptidase. The most prevalent penicillinase is β-lactamase.
Infections by penicillinase-producing bacteria are increasing, this can be attributed in part to the overuse of β-lactam antibiotics, this exerted a selection pressure in favour of strains of bacteria that were not susceptible.
Is there a way to prevent penicillinases altering the β-lactam ring activity?
It is possible to prevent inactivation by β-lactamase by the addition of clavulanic acid
in the drug formulation
. Both of these compounds work by binding irreversibly to the β-lactamase thus preventing it acting upon the β-lactam ring.
Some examples of β-lactam antibiotics in clinical use