How B-lactam drugs work

The enzyme that penicillin and other beta-lactam antibiotics target is transpeptidase, which is involved in cell wall synthesis. It creates peptide crosslinks in the cell wall. When transpeptidase is inhibited, the cells burst from osmotic pressure. The transpeptidase consists of an antiparallel beta sheet, with a small alpha helical subdomain on one side and a large alpha helical domain on the other. The surface of the beta sheet creates a groove where the substrate peptides can bind.

The beta lactam antibiotic . The groove also contains a that is important for the catalysis of the peptide bond formation. Instead of reacting with the normal peptide substrate, the serine residue has formed a with the carbonyl carbon of the beta lactam, as can be seen by its bond length (a C-O bond is 0.14 nm), and the increased distance between the carbonyl carbon and the (a normal C-N bond distance is 0.15 nm; this is almost double that distance). This prevents the normal substrate, the D-ala peptide fragments, from binding to the enzyme, preventing the crosslinking of the bacterial cell wall. Because the antibiotic is attached to the enzyme via a covalent bond, it doesn't come off easily, and the enzyme is essentially "dead". ^[2]

How do bacteria become resistant to penicillin and other beta lactam antibiotics? Some bacteria have an enzyme called penicillinase, which inactivates penicillin by cutting the beta lactam ring to form a carboxylic acid and an amine. This prevents the antibiotic from reacting with the serine residue in the transpeptidase, making it inactive. The gene for this enzyme is located on a bacterial plasmid, and can be transferred from one bacteria to another, causing antibacterial resistance to spread.

For more information about penicillin binding proteins, please see the Molecule of the Month page for penicillin binding proteins. [1]