How Penicillin Works

Penicillin is more than just a drug, it is a symbol of the introduction of pharmacy into our national conciousness. The very name is common to almost any vernacular. And yet, until my infectious diseases class the other day, I had no idea of the actual mechanism by which this archetypal drug overpowers a bacterial foe.

To understand the bacteriocidal action, one must first know a little bit about what bacteria look like. I envision the basic bacteria as a single cell, with little arms, or pili, coming off of it. This cell is surrounded by a membrane, just like human cells, and it also has a cell wall, a more rigid coating. There is a very high pressure inside the cell on the order of 10 to 20 atmospheres of pressure, which means that the bacteria can easily burst if they lack a strong cell wall.

Bacteria multiply very rapidly: roughly every 20 minutes the number of bacteria in a culture will double. This can have bad consequences for a host, since you need to mount a rapid and extensive immune response lest the infection get out of control. But it also illustrates one of bacteria's achilles heels: because they are constantly dividing, they need to keep making new cell materials, including those to build the new cell walls.

This is where penicillin comes in. One of the key components to the bacterial cell wall is a component called peptidoglycan. Think of this as a net surrounding the cell, made up of two sugars: N-acetylglucosamine and N-acetylmuramic acid. These two components make up a bunch of "ropes" which are then attached by short peptide strings to make the grid of the net.

This grid is what makes the cell wall strong; if it were just a bunch of parallel ropes, you can see how the pressurized bacterial cell could push apart two side-by-side chains and burst. In order to make the rigid grid, an enzyme called transpeptidase connects the little peptide strings perpendicular to the N-acetylglucosamine and N-acetylmuramic acid chains.

Penicillin acts by competitively inhibiting the transpeptidase enzyme, leaving the new bacteria without a strong net for a cell wall. Without this grid, the rapidly dividing bacteria cannot maintain a strong cell wall in themselves and their progeny, and so begin to pop, as seen in this video of e. coli treated with penicillin. For the chemically-curious, penicillin is a Beta-lactam, which means that it is a molecule with a square Beta-lactam ring as shown in the picture. This molecule looks like a dipeptide of 2 alanines, which is the peptide string that transpeptidase wants to tie to make a grid.

Interestingly, you may have heard of gram negative and gram positive bacteria. One of the major things that distinguish these two types of bacteria is the amount of peptidoglycan, or netting, that they have in their cell wall. Gram positive bacteria have a lot of peptidoglycan, and this thick net is what holds in the gram stain, hence their positivity. Gram negatives have a very thin layer of peptidoglycan, and so do not hold the stain. Since penicillin inhibits peptidoglycan synthesis, it is much better at attacking gram positive bacteria such as Staphylococcus or Streptococcus than gram negatives, such as E. coli.

Of course, the rapid rate of bacterial division also means that a mutant that is resistant to a drug will flourish. Nonetheless, penicillin remains one of the best drugs to use against a non-resistant bug: next time you are on an antibiotic, think of each little bacteria bursting out of its now-flimsy cell wall.