How Does Penicillin Work?

ANTIBIOTICS

The first antibiotic, penicillin, was discovered serendipitously in 1928 by Alexander Fleming. A medic by training Fleming went on to specialise in bacteriology before leaving his comfortable lecturing position for the trenches of World War I. He served as a medic in French field hospitals on the western front. There's no doubt that during his military service Fleming was exposed to the horrific toll that bacterial infection caused wounded troops. Many amputees died from non-life threatening surgery due to infections obtained in unsanitary field hospitals. But the discovery of penicillin revolutionised surgery, allowing patients to recover from infections that could otherwise kill them.

Alexander Fleming, perhaps not the happiest scientist there ever was. 

So effective was this wonder drug that Fleming was awarded the Nobel prize for Medicine in 1945. By this point, penicillin had saved thousands of lives both on and off the battlefield.

So how does Penicillin work? Well, to understand that one needs to understand the basics of cell biology. Cell biology studies with what cells are made of, and how they operate. A detailed understanding of cell biology is beyond the scope of this post, but it is useful to understand bacteria in the context of other forms of life. 

TYPES OF LIFE

It might seem surprising, but every living thing on the planet can be categorised into just there different branches on the complex tree life. These branches of life are called Prokaryotes, Eukaryotes, and Archaea. In addition there are also viruses. Viruses are often difficult to introduce when discussing simple life-forms because while they are much more simple than a bacteria cell, they are not always considered living cells. They have many of the characteristics of life, movement, sensitivity to their surroundings and so on, but unlike living cells they are unable to reproduce without a host cell. That is, they rely on infecting a bacteria or human cell to make more copies of themselves. For this reason, viruses are often considered nothing more than assembles of biomolecules, albeit, very interesting and often dangerous assemblies of biomolecules.

THE ARCHAEA

The Archaea branch of life contains the simpler organisms, the early forms of bacterial life on earth. They are single celled with an amazing ability to survive and adapt, often living in environments that we would consider hostile. For example, there are some Archaea bacteria that live in the very darkest depths of the ocean, in close proximity to hydrothermal vents. These living conditions contain extreme pressures and temperatures and there no sunlight. However, this proves to be no obstacle to these hardy organisms who thrive on the constant supply of noxious chemicals released from deep below the surface of the earth. 

THE PROKARYOTES

Like the Archaea, these are simple, unicellular organisms, but they tend to live in less hostile environments. These are the bacteria you are more likely to have heard of. The E.coli bacteria associated with food poisoning for example, or MRSA infections commonly contracted in hospitals. Prokaryotes are tough, adaptable, and capable of reproducing quickly making them potentially very dangerous. However not all of them cause disease in human (a quality known as pathogenicity). Some are actually beneficial to us, bacteria in our intestine actually help us digest food we eat, and produce vitamins for us in return.

THE EUKARYOTES

Finally, the eukaryotes. These are the most complicated organisms, and include some unicellular life such as yeast cells, but also the more complicated multicellular organisms. This includes everything from sponges to worms to humans. The individual cells that make up a human are much more complicated than an individual bacterial cell. This complexity comes at a price, namely the speed at which a human cell can make more of itself. Bacteria are very quick to reproduce but human cells, by comparison, are slow but make a more faithful copy of themselves. 

THE ANATOMY OF BACTERIAL CELLS
Bacteria themselves are incredibly interesting lifeforms. Although more simple than us they are  still very complex. They consist of a bunch of cell organelles, and some DNA wrapped up in a fatty skin called the cell membrane. Surrounding this cell membrane is a tougher shell called the cell wall. The cell wall is made of a tough material called peptidoglycan, and offers the bacteria some protection from the outside world. You can think if it as multiple layers of wire mesh; rigid, strong, but also flexible.

The anatomy of a bacterial cell. The yellow "skin" on the outside represents the cell membrane, and the cell wall. 

This peptidoglycan mesh is a composite of sugars and amino acids. The sugar components have the unwieldy name of N-acetylglucosamine, and N-acetylmuramic acid so for ease, biologists abbreviate these to simply NAG and NAM. NAG and NAM sugars are joined together in a chain, and individual chains become cross-linked with small protein molecules for extra strength and rigidity. As with many processes in biology the formation of a bacterial cell wall is facilitated by an enzyme, in this case, an enzyme called transpeptidase.

This image shows the function of the transpeptidase enzyme in making bacterial cell walls. The red and orange hexagons represent the individual NAG and NAM sugars that combine in long chains. The chains have small pieces of sticky protein (peptides)  hanging from every NAM molecule. The transpeptidase stitches each NAG-NAM chain together by fusing the peptides molecules together. These fused chains are the basic structure of a bacterial cell wall. 

Bacteria are constantly making and degrading their peptidoglycan cell walls during the process of cell division. It's a necessary part of how the divide and make more of themselves. Without the ability to make and repair their cell walls bacteria become flooded with water from outside the cell, and burst. A process called cytolysis. Therefore, the transpeptidase enzyme is essential for the survival of bacterial cells. Some antibiotics work by inhibiting the action of this essential enzyme. But how?

THE STRUCTURE AND FUNCTION OF ANTIBIOTICS
There are many different types of antibiotics, and they can be classified on the basis of their chemical structure, mode of action, or spectrum of action. As mentioned, Penicillin works by inhibiting bacterial cell wall synthesis, but other antibiotics work in different ways. What is it about penicillin that makes it work the way it does? Well, like a lot of biochemistry, it all comes down to to the atomic structure of the penicillin molecule. Fleming did not know this at the time of his discovery, but penicillin actually looks very like the peptide molecules used to strap the peptidoglycan chains together.

So, when we take penicillin to treat a bacterial infection we are presenting the bacterial transpeptidase enzyme with a choice. The enzyme can either, grab hold of the peptide molecule (D-Ala-D-Ala) like it's supposed to, or it can grab a molecule of penicillin. If it grabs a molecule of D-Ala-D-Ala then everything goes to plan, at least as far as the bacteria are concerned. Cell wall biosynthesis occurs normally, and the bacteria happily go about reproducing. However, if the transpeptidase enzyme grabs a molecule of penicillin instead of D-Ala-D-Ala, then the bacteria are in trouble. Penicillin will bind strongly to transpeptidase enzyme, effectively gumming up the works. We now have a situation much more like the image shown below.

Here, the penicillin molecule is represented as the yellow and black circle, jammed in the mechanism of the transpeptidase enzyme.

Here, the penicillin molecule is represented as the yellow and black circle, jammed in the mechanism of the transpeptidase enzyme. With penicillin gumming up the works it is not possible for transpeptidase to do it's job. The more penicillin we take the more this situation occurs, making it very difficult for the bacteria to reproduce. This mechanism of actions applies only to penicillin and antibiotics that look like penicillin such as amoxicillin. Different antibiotics work in slightly different ways, targeting different proteins that are important for bacterial cell survival.

ANTIBIOTIC RESISTANCE
Antibiotic resistance is becoming an increasing problem. It refers to the ability of some bacteria to keep reproducing despite the presence of antibiotics designed to kill them. So, how have these crafty bacteria overcome our sophisticated chemical weapons? The answer is evolution. Every generation of bacteria results in a slightly new organism. It's still a bacteria, but it's ever so slightly different from the "parent" that made it. Sometimes these differences are enough to result in interesting properties such as antibiotic resistance.

Antibiotic resistance stems from an overuse of antibiotics in medicine. This could be over-prescription by doctors, or people administering for diseases not associated with bacteria, such as colds, or flu, caused by viruses.  For any given infected individual it is unlikely that a single dose of antibiotics will wipe out every single bacterial cell in the body. Any cells that are left will produce offspring which become resistant to their hostile environment, and thrive in their new competition free zone. Next time these bacteria encounter this antibiotic they have already adapted to it, and produce their own chemical weapons to destroy ours.

CONCLUSION
So, there you have it. Penicillin works by preventing the construction of bacterial cell walls, causing bacteria to explode via an intake of water. Penicillin is just one of many types of antibiotic, which can produce their effects in different ways. Bacteria are adapting to these chemical weapons by producing chemical weapons of their own, destroying of the antibiotics before they can take effect. This has resulted in an literal arms race between us and the bacteria, but we are losing. The result is multidrug resistant bacteria such as MRSA which is having a pronounced effect on hospital patients worldwide. If we are to win this arms race we need think differently, and stop relying on brute force approaches.