Penicillin

Section 4 of 4

In 1928 a mould that drifted onto a dish of bacteria led to penicillin, one of the first antibiotics. Penicillin works by jamming an enzyme that bacteria need, with a small ring that springs open.

In September 1928 Alexander Fleming came back from a holiday to his laboratory at St Mary's Hospital in London. On one of his dishes of Staphylococcus bacteria, a blue-green Penicillium mould had grown, and around it the bacteria had gone. Fleming called the substance the mould made penicillin and published his findings in 1929. In 1940 and 1941, Howard Florey, Ernst Chain and Norman Heatley at Oxford worked out how to purify it and showed that it cured infections, first in mice and then in people. Fleming, Florey and Chain shared the 1945 Nobel Prize in Physiology or Medicine.

Penicillin G, C₁₆H₁₈N₂O₄SAn antibiotic made by Penicillium mould. A four-membered ring of three carbon atoms and a nitrogen atom, with a C=O on one carbon, shares its nitrogen and one carbon with a five-membered ring holding a sulfur atom. A side chain ends in a benzene ring.SOOHOONNH
Penicillin G, C₁₆H₁₈N₂O₄S. The square is the four-membered beta-lactam ring, joined to a five-membered ring with a sulfur atom (S). The side chain on the left ends in a benzene ring.

A squeezed ring

In 1945 Dorothy Hodgkin used X-rays to work out penicillin's structure, and it showed a ring of just four atoms: three carbons and a nitrogen, with a C=O on one carbon. A C=O next to an N in a chain is the amide link that joins amino acids, and an amide closed up into a ring is called a lactam. Penicillin's is a beta-lactam.

In lesson 6 you saw that rings of 5 and 6 atoms let their bonds sit close to their natural angles, and that a three-membered ring is squeezed and reactive. A four-membered ring is a square, with corners of about 90°. Its carbon atoms want 109.5°, and the C=O carbon wants 120°, so the ring is strained, ready to spring open.

Jamming the wall builder

A bacterium wraps itself in a tough cell wall, made of long sugar chains tied together by short chains of amino acids. An enzyme ties the knots: it grabs the end of a short chain, which ends in two D-⁠alanines, the mirror-image hand of the alanine in your proteins. Penicillin mimics that end, with its atoms where the end's atoms would sit, so it fits the enzyme's active site.

There, an -⁠OH group of the enzyme, on a serine, meets the C=O carbon of the strained ring, the same kind of -⁠OH that aspirin's ethanoyl group joins. The ring springs open, and penicillin ends up bonded to the enzyme's oxygen. The enzyme is jammed for good.

Penicillin's four-membered ring opens onto the enzyme Left: penicillin's four-membered ring, a square of three carbon atoms and a nitrogen atom, with a C=O on the bottom left corner. The corners are squeezed to 90 degrees. Below, an -OH group of the enzyme points up at the C=O carbon. Dotted stubs lead to the rest of the molecule. An arrow points right. Right: a new bond, in amber, joins the C=O carbon to the enzyme's oxygen, the C-N bond along the bottom of the ring has broken, and the nitrogen carries a hydrogen. The ring is open and penicillin is fixed to the enzyme. NOOH 90° OONH squeezed ring ring opened enzyme enzyme
The enzyme's -⁠OH group meets the C=O carbon of the squeezed ring. The C–⁠N bond breaks, the ring opens, and a new bond (amber) fixes penicillin to the enzyme.

With its wall builders jammed, a growing bacterium cannot tie its wall together. Water flows into the cell, the weakened wall gives way, and the cell bursts. Your own cells have no cell wall, so penicillin leaves them alone.

Quick check

What makes penicillin's four-membered ring so ready to spring open?

That's the end of lesson 19

In this lesson you found out:

  • How a medicine fits a pocket in its target protein
  • How aspirin came from willow bark, and how it blocks an enzyme
  • Why the hand of a medicine molecule matters
  • How penicillin's squeezed ring jams the enzyme that builds a bacterium's wall
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