In this article we will discuss about:- 1. Discovery of Penicillin 2. Structure and Types of Penicillin 3. Antibiotic Spectrum 4. Mechanism of Action.
Discovery of Penicillin:
The first penicillin discovered by Alexander Fleming in 1929 as a product of fungus Penicillium notatum was the penicillin G. Also, penicillin G became the first clinically effective antibiotic. Even with the use of sulfa drugs, most infectious diseases were not under control in the 1930s.
However, in 1939, Howard Florey and his colleagues, spurred on by the beginning of World War II, developed commercial production process of penicillin using Penicillium chrysogenum mould. The new antibiotic was dramatically effective in controlling staphylococcal and pneumococcal infections among military personnel and was more effective for treating streptococcal infections than the sulfa drugs.
By 1945 and the end of the World War II, penicillin became available for public use, and pharmaceutical companies began to look for other antibiotics for successful treatment of other infectious diseases.
Structure and Types of Penicillin:
Penicillins are a group of β-lactam antibiotics consisting of natural penicillins and semisynthetic penicillins. The basic structure of all penicillins, natural and semisynthetic, is 6-aminopenicillanic acid composed of a four membered heterocyclic β-lactam ring fused with a five membered (benzylpenicillin), penicillin V (Phenoxymethyl penicillin), thiazolidine ring as shown in Fig. 45.6.
This basic structure combines with N-acyl group which is variable and shows structural differences in different type of penicillins. The N-acyl group is the side chain attached to the amino group of 6-aminopenicillanic acid. However, there are three natural penicillins that are produced directly and can be obtained from the fermentation Iiquours of Pencillium.
These are penicillin G and penicillin F (phentenyl penicillin). Natural penicillins are obtained as salts of sodium (Na) or potassium (K) or procaine. The structures of natural penicillins as Na-salts are shown in Fig. 45.7.
The natural penicillins have been structurally modified in the laboratory to enhance their efficacy. These are said to be semisynthetic and were developed to add mainly three properties lacking in penicillin G.
These properties are:
(i) Resistance to β-lactamase (penicillinase),
(ii) Ability to remain active in acidic pH, and
(iii) To enlarge the antibiotic spectrum.
There are a large number of semisynthetic penicillins ampicillin, amoxycillin, azlocillin, carbenicillin, cloxacillin, methicillin, oxacillin, phenethecillin, piperacillin, ticarcillin, etc. All of the semisynthetic penicillins have in common the β-lactan-thiazolidine (6-amino penicillanic acid) with different N-acyl groups.
The N-acyl group of some important semisynthetic penicillins and their properties is given in Table 45.11.
Antibiotic Spectrum of Penicillin:
Among all the penicillins, penicillin G (benzylpenicillin) is the most active . It is a narrow-spectrum antibiotic as its activity is primarily restricted to gram-positive bacteria especially gram- positive cocci and some spirochaetes. Penicillin G is not active against gram-negative bacteria because these bacteria are imprermeable to the antibiotic (it is found active against Neisseria, a gram-negative gonococcus bacterium).
This antibiotic is administered by intramuscular injection and is non-toxic to humans except in very rare cases where it may cause a severe hypersensitive reaction (anaphylaxis) which may prove fatal. Penicillin G is quickly inactivated at an acidic pH and by β-lactamase (penicillinase).
It is quickly absorbed and also quickly excreted hence retained for a short while in the body. To increase its retention time in the body, the antibiotic is combined with procaine. Penicillin V (phenoxymethylpenicillin) resembles penicillin G in most of its properties except that it is more stable at an acidic pH and, therefore, can be taken orally. This antibiotic is credited to be the first penicillin taken orally clinically.
Many semisynthetic penicillins are broad-spectrum antibiotics and are quite effective against gram- negative bacteria in addition to gram-positive ones. For example, carbenicillin, oxacillin and ticarcillin are also active against gram-negative bacteria like Pseudomonas and Protens.
Ampicillin was the first broad-spectrum penicillin developed. It is active against both gram-positive and some gram-negative bacteira. Amoxycillin is closely related to ampicillin and has a similar antibiotic spectrum.
Mechanism of Action of Penicillin:
The most crucial feature of penicillin molecule is its β-lactam ring, which appears to be essential for activity. All penicillins therefore are included in the family of β-lactam antibiotics which includes also cephalosporins. The β-lactam antibiotics are potent inhibitors of cell wall synthesis. The mechanism of the action of penicillins is still not completely understood.
It has been proposed that penicillins inhibit the enzyme trans-peptidase catalysing the transpeptidation reaction because of their structural similarity. Transpeptidation reaction is an important feature of bacterial cell wall synthesis and results in the cross-linking of two glycan-linked peptide chains of peptidoglycan (Fig. 45.8), the main constituent of bacterial cell walls especially those of gram-positive ones.
However, the trans-peptidase enzymes are capable of binding the penicillin or other β-lactam antibiotics. Thus, these trans-peptidases are known as penicillin binding proteins (PBPs). When the PBPs bind penicillin forming penicillin-PBP-complex, they fail to catalyse the transpeptidation reaction, but the cell wall continues to be formed.
The newly synthesised wall is no longer peptide-inter-bridged (cross-linked) and, therefore, the synthesis of complete, fully cross-linked peptidoglycan is blocked. As a result of defective peptidoglycan, the newly synthesised cell wall can not maintain strength and fails protecting bacterial cells against osmotic stocks which cause expansion and ultimately the bursting of plasma membrane resulting in death of the cell. This bursting process is called osmotic lysis.
However, more recently it has been discovered that penicillin-PBP-complex stimulates the release of autolytic enzymes (autolysis) that digest the existing cell wall. There is some evidence that penicillin may stimulate special proteins called bacterial holins which form holes or lesions in the plasma membrane.
This would lead two possibilities:
(i) Direct membrane leakage and
(ii) The movement of peptidoglycan hydrolases through the holes disrupting the peptidoglycan.
In both cases the ultimate result would be the lysis of the cell. Apparently, the mechanism of penicillin action is more complex than previously imagined and attracts more attention.