Although used in the singular, the term penicillin does not refer to a single drug, but to a large group of molecules used in the treatment of numerous bacterial infections.
The discovery of penicillin
The discovery of penicillin is attributed to the physician and biologist Alexander Fleming.
In 1928, Fleming conducted research on some pathogenic bacteria, cultivating them in special culture plates. One of these plates was contaminated by a fungus, Penicillium notatum (now known as Penicillium chrysogenum ). The thing that struck Fleming the most, was not the fact that the fungus had grown in the culture medium, but the fact that it was able to kill all the bacteria that were around it, creating an aura of inhibition of bacterial growth around to their colonies.
Fleming immediately understood that the antimicrobial activity could be attributed to a substance produced by that same fungus and isolated it in an attempt to identify this particular substance.
After several attempts, Fleming finally succeeded in isolating from his fungus a sort of "juice" and called it penicillin .
Fleming administered his penicillin to animals infected with the same bacteria that were sensitive to this substance in vitro and succeeded in achieving positive results. The success achieved in animals prompted Fleming to attempt penicillin administration even to patients who had contracted infections.
In 1929, Fleming decided to publish his research and the results of his clinical tests. Unfortunately, due to a series of unfavorable circumstances and due to the impossibility of purifying the penicillin in such a way as to make it usable in full safety and also on a large scale in men, this promising antimicrobial was set aside.
Ten years later, a group of English chemists (including Abraham, Chain, Florey and Heatley) - after extensive research and various attempts - finally succeeded in isolating the precious antibiotic. In 1941, clinical trials began to establish the efficacy and safety of penicillin in human infections and in 1943 began its production on a large scale.
General structure of penicillins
The penicillin obtained from the cultures of P. notatum, in reality, was not a single molecule, but a mixture of different compounds that differed due to some variations in their chemical structure. The research carried out later highlighted this fact; furthermore, it was discovered that - by making changes to the composition of the culture medium - different molecules could be obtained.
More precisely, it was discovered that by adding phenylacetic acid to the culture medium, penicillin G (now known as benzylpenicillin ) was obtained. If, on the other hand, large quantities of phenoxyacetic acid were present in the culture medium, penicillin V was obtained (now known as phenoxymethylpenicillin and considered the progenitor of acid-resistant penicillins).
It was also discovered that by eliminating certain elements from the fungus culture medium, the main nucleus of all penicillins could be obtained: 6-aminopenicillanic acid (or 6-APA ).
The 6-APA contains within it the pharmacophore of penicillins, that is that part of the molecule that confers the antibiotic activity to this type of drugs. This pharmacophore is the β-lactam ring .
Thanks to the discovery of 6-APA it was possible to obtain - synthetically - numerous new types of penicillins, some of which are still used in therapy.
As for the completely natural penicillins, the only ones still used today in therapy are benzylpenicillin and phenoxymethylpenicillin.
Indications
For what it uses
Thanks to the availability of numerous and different types of molecules, penicillins are indicated for the treatment of a wide variety of infections caused by multiple bacteria, both Gram-positive and Gram-negative.
Action mechanism
Penicillins exert their antibiotic action by inhibiting the synthesis of peptidoglycan (the bacterial cell wall).
Peptidoglycan is a polymer consisting of two parallel chains of nitrogenated carbohydrates, joined together by transverse bonds between amino acid residues. These transverse bonds are formed thanks to a particular enzyme called transamidase .
The penicillins bind to the transammidase preventing the formation of the aforementioned transverse bonds, thus generating weak areas within the peptidoglycanic structure that lead to cell lysis and the consequent death of the bacterial cell itself.
Penicillin resistance
Some types of bacteria are resistant to penicillins thanks to the production of a particular enzyme, β-lactamase . This enzyme is able to hydrolyze the β-lactam ring of penicillins, inactivating them.
To overcome this phenomenon, penicillins can be administered in association with other particular types of molecules, β-lactamase inhibitors . These compounds are able to hinder the action of bacterial enzymes, thus allowing penicillins to carry out their therapeutic action.
However, antibiotic resistance is not only caused by the production of these enzymes by bacteria, but can also be caused by other mechanisms.
These mechanisms include:
- Alterations in the structure of antibiotic targets;
- Creation and use of a metabolic pathway different from that inhibited by the drug;
- In this way, changes in cell permeability to the drug hinder the passage or adhesion of the antibiotic to the bacterial cell membrane.
The development of antibiotic resistance has increased considerably in recent years, mainly due to the abuse and the misuse that is made of it.
Therefore, even a class of molecules as vast and powerful as that of penicillins, risks becoming more unusable and ineffective every day due to the continuous development of numerous resistant bacterial strains.
Classification of penicillins
Penicillins are generally classified according to their route of administration, their action spectrum and their chemical and physical characteristics.
Penicilline delay
These penicillins are found in the form of salts and are used parenterally.
The salified form of the drug allows a slow release inside the body once it has been administered.
This type of penicillin is used when a prolonged release of the drug is needed to keep the plasma antibiotic concentration constant over time.
Benzylpenicillin benzathine and procainic benzylpenicillin are part of this category.
Acid-stable penicillins
Penicillins degrade easily in an acidic environment, therefore, they can also degrade inside the stomach. In fact, some types of penicillins must be administered parenterally, in order to avoid their degradation.
By making some small changes in the chemical structure of penicillins, it is possible to obtain stable molecules even in an acid environment, thus allowing oral administration.
Acid-stable penicillins all derive from phenoxymethylpenicillin (penicillin V). These include pheneticillin, propicillin, phenbenicillin and clometocillin .
Resistant β-lactamase penicillins
As the name implies, the penicillins belonging to this category are resistant to the action of β-lactamases.
This type of penicillin is usually administered parenterally.
Methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin and flucloxacillin belong to this category.
Broad spectrum penicillins
These penicillins have a broad spectrum of action; therefore, they are useful in treating numerous types of infections.
Some of the penicillins belonging to this category can be administered orally, while others are administered parenterally, but all are sensitive to bacterial β-lactamases. Therefore, very often, these penicillins are administered in combination with β-lactamase inhibitors.
Ampicillin, pivampicillin, bacampicillin, metampicillin, amoxicillin, carbenicillin, carindacillin, carfecillin, mezlocillin, piperacillin, azlocillin, sulbenicillin, temocillin and ticarcillin belong to this category.
Β-lactamase inhibitors
These compounds are not penicillins, but possess a chemical structure very similar to that of 6-APA. They are able to inhibit bacterial β-lactamases, thus preventing the degradation of penicillins and allowing them to perform their therapeutic action. Moreover, they also have a weak antibacterial action.
Clavulanic acid, sulbactam and tazobactam are β-lactamase inhibitors.
Penicillin allergy
Penicillins are a class of drugs that can easily trigger allergic reactions. Generally, these reactions are mild and delayed in nature and can occur in the form of rashes and itching.
Very rarely, intolerance manifests itself in an acute and severe manner, but - if this occurs - the drug should be stopped immediately.
In patients with a history of acute and severe penicillin intolerance, treatments with other types of β-lactam antibiotics (such as, for example, cephalosporin-based treatment) are also contraindicated.
However, there may be cases in which individuals become aware of penicillins without being aware of them; this can happen with the intake of foods or drugs contaminated by these antibiotics.
The penicillins should be prepared in separate plants and distinct from those used for the production of other drugs, in order to avoid accidental contamination and the possible sensitization of the individuals who will then go on to take the contaminated drug.
As far as food is concerned, however, animals to which antibiotics have been administered should stop taking the drug for a long time before being destined for human consumption.
In case of allergy to penicillins, alternative antibiotics can be given, such as erythromycin (the progenitor of macrolide antibiotics) or clindamycin (an antibiotic belonging to the class of lincosamides ).
