Fleming published his finding in 1929, describing a mold (Penicillium notatum) that produced an antibacterial substance he called "penicillin" — and then the discovery essentially lay dormant for ten years. In 1939, Howard Florey and Ernst Chain at Oxford purified it and tested it in mice. The first human patient was treated with purified penicillin in 1941. Fleming, Florey, and Chain shared the 1945 Nobel Prize in Medicine.
Structure: the β-lactam ring that defines everything
Penicillin G (benzylpenicillin, C₁₆H₁₈N₂O₄S) has two key structural features: the β-lactam ring (a four-membered lactam ring under significant angular strain — bond angles of 90° vs optimal ~120° for sp²) fused to a thiazolidine ring (five-membered, containing sulfur). This bicyclic fusion maintains the β-lactam's strained geometry, maximizing its electrophilic reactivity.
The mechanism: attacking the bacterial cell wall
Bacteria (unlike animal cells) are surrounded by a peptidoglycan cell wall that provides rigidity and osmotic protection. Transpeptidases (Penicillin-Binding Proteins, PBPs) catalyze the final cross-linking step of peptidoglycan synthesis. Penicillin mimics the D-Ala–D-Ala dipeptide substrate of transpeptidases — the enzyme "mistakes" penicillin for its substrate and attempts catalysis, forming a covalent ester with the active-site nitrogen that irreversibly blocks the enzyme. Without functional transpeptidase, dividing bacteria cannot complete their cell wall, accumulate structural defects, and lyse.
Why penicillins are safe for humans
Penicillin's selective toxicity is nearly perfect because transpeptidases do not exist in eukaryotic cells — animal cells have no peptidoglycan wall. The therapeutic window is extraordinarily wide. Penicillin allergic reactions (1–5% of users) are not pharmacological effects but immune responses to the β-lactam acting as a hapten.