How does penicillin work?

According to their mechanism of action, antibiotics can be divided into three large groups:

• Those inhibiting cell wall synthesis
• Those inhibiting protein synthesis
• Those inhibiting nucleic acid synthesis

Penicillins and related compounds all prevent susceptible bacteria from creating a cell wall.

Why is a cell wall important? Like most biological membranes, the cell membrane (not 'wall') of bacteria is semipermeable - that is, while water can pass through the cell membrane without too much trouble, many osmolytes are prevented from doing this. As you may remember from physiology, this allows for osmosis to occur. The inside of a bacterium is packed with enzymes and other molecules, and its osmoloarity is significantly higher than the average extracellular osmolarity. Thus, there is an osmotic pressure that would tend to 'force' water molecules into the cell. All things being equal, bacteria would therefore all swell and eventually burst within a few seconds.

Enter the cell wall. This structure's primary function is to resist the tendency for the bacteria to swell and burst due to osmosis. (More scientifically, it resists the turgor pressure.) So, it's not hard to imagine why any compound that blocked a bacterium's cell wall synthesis would effectively kill it. And this is exactly what penicillin does.

You can stop reading right now if that's enough detail for you. However, if you want specifics, read on...

A large component of all bacterial walls is a substance known as peptidoglycan. Gram positive bacteria have cell walls made almost exclusively of peptidoglycan, whilst the proportion of the Gram negative bacterial cell wall it constitutes is considerably less.

Peptidoglycan is principally made from two sugar molecules. Their names are N-acetylglucosamine and N-acetylemuramic acid, but we can call them NAG and NAM. Bacteria synthesise long linear chains of these two sugars, alternating between a NAG and a NAM.

Attached to each NAM, however, is a chain of a few amino acids (an oligopeptide). [Interestingly, these amino acids aren't found in proteins, and this may allow them to escape degradation by our most common proteases (enzymes that cleave proteins).] To complete the structure of peptidoglycan, these oligopeptides are cross-linked to a neighbouring chain's oligopeptides to form a strong mesh.

What penicillins do is to irreversibly bind to the bacterial enzyme that cross-links these chains. The unfortunate enzyme's name is transpeptidase, though is sometimes (rather anthropocentrically!) referred to as "penicillin-binding protein". This binding deactivates the enzyme, and so no crosslinking of the 'amino sugar' chains can take place. And we've already mentioned how catastrophic this is for an aspirant bacterium...

Incidentally, it is also immediately clear why penicillins tend to work better on Gram positive than Gram negative organisms - Gram positive organisms are simply more dependent on peptidoglycan for their cell walls.

One other interesting point: you may know that tears have weak antibacterial properties. This is principally due to the fact that they contain lysozymes. These compounds go to work by breaking down the bonds between the sugar residues (NAM and NAG). The end result is almost as if tears had secreted their very own penicillin molecules!