Mechanism of action
Penicillins have a bacteriolytic effect during the cell division of bacteria, namely during the rebuilding of the cell wall, by interfering with the synthesis of the cell wall, preventing the internal cross-linking there and thus weakening the cell wall so that it bursts under stress. In particular, gram-positive bacteria that divide die under the influence of penicillin. The basic structure of penicillins consists of 6-aminopenicillanic acid, a bicyclic dipeptide of cysteine (L-configured) and valine (D-configured, after configuration reversal in the biosynthetic pathway). This so-called beta-lactam ring is bound (in the then opened state) by the bacterial enzyme D-alanine transpeptidase, which is responsible for the cross-linking of peptidoglycans in the bacterial cell walls of Gram-positive bacteria. The enzyme is especially required in dividing bacteria, since in these the rigid cell wall must be opened and at least partially re-synthesized. Since the binding to D-alanine transpeptidase is irreversible, the cell wall can no longer be synthesized and the Gram-positive bacterium loses its most important protective cover. In addition, the constant build-up and degradation of the defective cell wall leads to toxic degradation products.
The effect of penicillins therefore only affects reproducing bacteria, but not non-dividing ones: The antibiotic no longer affects these, because no cell wall synthesis has to take place - it is already complete and therefore no longer forms a point of attack for penicillin. However, bacteria that do not reproduce do not pose a threat to the host organism and are relatively quickly rendered harmless by the patient's own immune defence system. If, on the other hand, they re-enter a multiplication cycle, the cell wall is again partially degraded and must be re-synthesized; such bacteria are therefore attackable again by penicillins. For this reason, penicillins must continue to be administered for a certain follow-up period after the symptoms have subsided.
Penicillins are therefore only effective if the bacteria are otherwise unhindered in their growth; thus, penicillins should not be administered together with drugs that prevent the bacteria from multiplying, since otherwise one would therapeutically block even the starting point of the penicillin's mode of action.
Penicillins not only act on bacteria, including cyanobacteria, but they also block the division of cyanelles, the photosynthetically active organelles of the Glaucocystaceae (an algae family) and the chloroplasts of bladder cap mosses. However, they have no effect on the division of plastids of more highly developed vascular plants, such as tomatoes. This is an indication that in higher plants, due to evolutionary changes in plastid division, β-lactam antibiotics generally no longer have any effect on chloroplasts.
Penicillin G and V are not effective against Gram-negative bacteria (with the exception of Gram-negative cocci such as Neisseria), which have an additional outer membrane above their cell membrane. This makes it impossible for penicillin to attack, as it has to interfere with the formation of the underlying peptidoglycan layer. Therefore, the use of penicillin G and V is only useful against gram-positive bacteria. Structural variants such as aminopenicillins are used against Gram-negative bacteria.
Resistances
Numerous - but not all - clinically occurring bacteria are already resistant to penicillin G today, which has led to a number of further developed β-lactam antibiotics. One exception, for example, is the bacterium Treponema pallidum (causative agent of syphilis/Lues), against which there has been no development of resistance to penicillins to date.
The problem of cross-resistance remains critical, which means that germs that have once developed resistance to penicillins also become insensitive to other β-lactam antibiotics (e.g. cephalosporins).
Resistant mutants would not actually cause any harm, as they occur only in small numbers. However, if the penicillin acts on the other, non-resistant bacteria and eliminates them, a resistant bacterium can reproduce much more easily and thus becomes a danger, as it passes on its resistance to the subsequent generations. Through the exchange of resistance genes between different bacterial species, antibiotic resistance is also passed on to other species. Methicillin resistance in Staphylococcus aureus is particularly feared.
The process of resistance development is a very illustrative example of Darwinian evolutionary theory (natural selection); due to rapid division and generation succession, resistant bacteria adapted to their environment are selected and form the basis for later generations. The formation of penicillin-resistant strains is considered one of the first experimental evidences of observed microevolution. The biological basis of the group of agents is the competition between the two strains of organisms, fungi and bacteria, which depend on the same resources, with the fungi protecting themselves against the bacteria with antibacterial growth-inhibiting substances.
Side effects
As with all antibiotics, resistance can also develop to penicillins. The frequency of allergies to penicillin therapy is much lower than previously assumed (). Allergic reactions can range from mild reddening of the skin to anaphylactic shock.
Penicillins can kill useful bacteria such as those of the intestinal flora, especially broad-spectrum penicillins, which are also effective against Gram-negative bacteria. In the worst case, harmful microorganisms can thus spread in the intestine and lead to antibiotic-associated colitis.
Another rare (with a probability of about three per thousand) adverse effect is the triggering of epileptic seizures.
