Penicillin is one of the Broad-Spectrum Antibiotics; as its name, there is penicillin in the molecule of it and this can allow it to break the cell walls and play a role of disinfecting during the Cell reproductive period. Penicillin is called as Penicillin G as well. It is belonging to Beta-Lactams type antibiotic; this category of antibiotics includes Cephalosporin and Cephamycins as well. Penicillin is a commonly used antibiotic but every time before we use it we have to have a skin test in order to avoid the irritability of the organism.


Here is some history of penicillin.

Back in 1877, Pasteur and Joubert discovered certain moulds which could produce toxic substances which can kill bacteria. However, why are these substances not being used? The reason is that they are toxic to humans. However, even though it cannot be used on human body it does not mean that it is useless. Instead of being a medicine it became a potential source of antibacterial agents. In 1928, scientist Fleming noticed that a bacterial culture that had been left outside for few weeks had become infected by a fungal colony. But the most interesting thing about this observation is that surrounding the fungal colony the bacterial colonies were all dying. Because of this, Fleming started his study about this observation and finally, he correctly concluded that the fungal colony was producing an antibacterial agent which was spreading into these areas. After some more further studies, he was able to show that the antibacterial is a relatively rare species of Penicillin. Since Penicillin appears in Fleming’s lab there is Penicillin spore appeared in the other labs in the same building. As the study shows, this happened because the spore was carried by the air currents and blow through the window of Fleming’s lab. A period of time after the observation Fleming found out the relationship between the fungus and the Penicillin: when the weather is cold the fungus is going to produce Penicillin; when it is a warm weather the antibacterial properties of Penicillin is going to be revealed. However, if the weather had been consistently cold, the bacteria would not have grown significantly and the death of cell colonies close to the fungus would not have been seen. Alternatively, if the weather has been consistently warm for a long period of time, the bacteria would have outgrown the fungus and as a result, there will be little Penicillin has been produced. Although Fleming spent several years investigating the novel antibacterial extract and showed it to have significant antibacterial properties and is remarkably non-toxic to mammals, unfortunately, Fleming was unable to isolate and purify the active principle, so came out a conclusion that Penicillin was too unstable to be used clinically.

After eleven years the problem of isolating Penicillin was solved in 1938 by Florey and Chain by doing the process of freeze-drying and chromatography, and this allows the isolation of the antibiotic under a much milder condition. By 1941 Florey and Chain were able to bring out the first clinical trials on crude extracts of Penicillin and achieved spectacular success. Furthermore, the aim of the further study is to discover a new type of agent which can be produced in large quantities and this was developed in the USA; the result of this improvement is that there was enough Penicillin to treat the casualties arising from the World War Two. This can show this new drug saved a lot of lives at that time.

Even though Penicillin saved a lot of lives and was now widespread, but the structure of the compound was still not settled, and because of its unusual structures, there is furious debate happened just because of its structure. Finally, the ‘fight’ has been solved by Dorothy Hodgkins in 1945. In that year she established the structure by X-ray crystallographic analysis. The structure gives a big boom to the Chemistry world at that time because the Penicillin is a molecule which has a complicated structure, and this is the reason why Fleming failed when he is trying to purify the Penicillin

Although Penicillin has a highly strained molecule as the study shows still there is a scientist who successfully did the full synthesis of the Penicillin in 1957 and the name of this Scientist is Sheehan. However, this whole synthesis was too involved to be of commercial use. After a year, Beechams isolated a biosynthetic intermediate of Penicillin which is called 6-aminopenicillin which is abbreviated to 6-APA. This development provided the starting material for a huge range of semi-synthetic Penicillin. Since then, because Penicillin is more easy to make this makes Penicillin has been widely used carelessly. As the result of this, the Penicillin-resistant bacteria have evolved and become a problem. In 1976 when Beecham made a natural product called Clavulanic acid, it proved highly effective in protecting Penicillin from the attacks made by bacterial enzymes.

Coming up some more Chemistry details about the Penicillin.


As we know Penicillin is highly unstable-looking. It contains a four-membered Beta-Lactam ring which is fused to a five-membered thiazolidine ring.(Figure 1) And as an overall shape (Three-dimensional shape) for the Penicillin, it looks like a half-open book just like it shows in (Figure 2)










(Figure 1) The structure of Penicillin                                                                        (Figure 2) The half-open book look










(Figure 3) The Acyl side chain

The acyl side chain (Fig (2.1.1).3) varies, and it depends on the components of the fermentation medium. Here is an example: corn steep liquor contains high levels of Phenylacetic acid (PhCH2CO2H) and it will give out Benzylpenicillin (Penicillin G; R=Benzyl: C6H5CH2). If a fermentation medium contains Phenoxy acetic acid (PhOCH2CO2H), in this case, it will give out Phenoxy methyl penicillin (Penicillin V; R=PhOCH2)

Now let us talk about the product of the Penicillin after using Phenylacetic acid (PhCH2CO2H) as the fermentation medium - Penicillin G. (Figure 4)











(Figure 4) Penicillin G’s structure


Benzyl Penicillin is active against the range of bacterial infections and also it will work for the side-effects for the majority of the patients. However, it cannot be taken orally because it will break up in the stomach acid; also it has a relatively narrow spectrum for the activity and because of this Benzyl Penicillin will not work for some of the bacteria. The reason for that is the microorganism will produce an enzyme called Beta-lactamase. Because of the Beta-lactamase, the structure will become inactive because Beta-lactamase can hydrolyze the Beta-lactam. Thus, there is a lot more scope for producing analogues with improved properties. Before we are going to study other types of Penicillin we are going to have a look at the Penicillin’s mechanism of action.

In order to understand what is going on when Penicillin comes into contact with the bacterial cells, we may first have to look at the structure of the bacterial cell wall and the mechanism by which it is formed. Bacterial need the cell wall, for it helps them to survive from a large range of environmental conditions, like variations of PH, temperature, or even pressure. If the bacteria do not have a cell wall the water will go into the cell easily; we are not saying that the cell wall of the bacterial is totally water resistant but most of the water will get blocked outside the cell due to the cell wall and this prevents the cell swelling. However, not every single cell will have a cell wall, like Mammalian cells, and this makes Mammalian cells a perfect target for antibacterial agents to attack just like Penicillin. Here is an example of a cell wall of a Peptidoglycan structure, in simple words, it is made up of peptide and sugar. (Figure 5)













(Figure 5) Cell wall’s structure


The cell wall is parallel series of sugar backbones which maintains two types of sugar: one is the NAM the other is the NAG and the peptide is bonded to the NAM sugars, which will form the D-amino acids. (Figure 6) In human Biochemistry, only L-Amino acid exists. Because the bacteria have racemase enzyme, so the L-Amino acid gets converts into the D-Amino acid. (Figure 6) Finally, the peptide chains are linked together because of the displacement of the D-Amino.













(Figure 6) L, D-Amino Acid


There are about 30 enzymes that attend the biosynthesis of the cell wall, but the process which really inhabited the Penicillin is the final cross-linking reaction. This makes the cell walls no longer link with each other, thus, as a result, the cell is no longer prevented from the swelling and bursting, because the cell wall becomes fragile. The enzyme side of the cross-linking process is known as Transpeptidase enzyme. There is a huge difference in the thickness of the cell wall between Gram-positive and Gram-negative bacteria. The cell wall in the Gram-positive bacteria is known as 50-100 peptidoglycan layers, but in the Gram-negative bacteria, it consists of only two layers.

After a brief look at the structure of the cell wall and the Penicillin’s mechanism of action, let us move onto the next step which is the exciting part – Methods of analogues then synthesizing Penicillin.

In the analogues of Penicillin G, we need to learn how it can be synthesized in a more stable and active way (because the way which Sheehan did is too complicated and also it has a too low yield (only 1%) for it to be practical). Also, this limits the options for the fermentation methods or semi-synthesis procedures.

First of all, we are going to talk about the Fermentation. At the beginning, the only way to prepare varies of Penicillin was just to various different types of fermentation conditions. However, there was a limitation of the sorting of the carboxylic acid which was accepted by the biosynthetic route. There is another major disadvantage which was the tedious and time-consisting nature of the method.

Second, coming up is the Semi-synthetic procedure. In 1959, Beechams isolated the biosynthetic intermedia of Penicillin from Penicillium Chrysogenum grown in a fermentation medium which is short in a carboxylic acid.

This is roughly about our Penicillin. Here are some history and some chemistry in there which are all around it.