Note that there are two heterocyclic rings to which various side chains attach. All have a C=O group that comes from a carboxyl group COOH. Although the natural penicillins are excellent antibiotics, their properties depend on the side chain. For example, simply changing the side chain to the phenoxymethyl of Penicillin V confers much better acid stability so that oral administration is not so badly beset by the low pH in the stomach. In other words, Penicillin V has relatively good acid stability.

In the search for better penicillins, only those side chains accepted by the producing organisms (usually Penicillium notatum) could be made. A great advance was using the enzyme penicillin acylase to cleave off the side chain. New side chains could be attached, and many dozens of new penicillin call semi-synthetic have been made and evaluated. Commercial manufacturing relies on immobilizing the enzyme for economic reuse.