Generality
Beta-lactams (or β-lactams) constitute a large family of antibiotics, comprising numerous molecules that have in common the central nucleus at the base of their chemical structure: the beta-lactam ring, also known more simply as beta-lactam .
The beta-lactam ring - besides being the central nucleus of this class of antibiotics - is also the pharmacophore of these molecules, that is, it is the group that confers the antibacterial properties typical of these drugs.
Beta-lactam antibiotic classes
Within the large family of beta-lactams we find four classes of antibiotics, penicillins, cephalosporins, carbapenems and monobactams .
The main characteristics of these drugs will be briefly described below.
penicillins
Penicillins are antibiotics of natural origin, as they are derived from a fungus (ie, a fungus).
More precisely, the founders of this class of antibiotics - penicillin G (or benzylpenicillin ) and penicillin V (or phenoxymethylpenicillin ) - were isolated for the first time from cultures of Penicillium notatum (a mold now known as Penicillium chrysogenum ).
The discovery of penicillin is attributed to Alexander Fleming who, in 1928, observed how Penicillium notatum colonies were able to inhibit bacterial growth.
However, benzylpenicillin and phenoxymethylpenicillin were isolated only ten years later thanks to a group of English chemists.
From that moment on, the great development of research in the field of penicillins began, in an attempt to find new compounds that were increasingly safe and effective.
Thousands of new molecules were discovered and synthesized, some of which are still used in therapy.
Penicillins are antibiotics with bactericidal action, ie they are able to kill bacterial cells.
Among the many molecules belonging to this great class, we recall the ampicillin, amoxicillin, methicillin and oxacillin.
Cephalosporins
Cephalosporins - such as penicillins - are also antibiotics of natural origin.
The molecule considered the forefather of this class of drugs - cephalosporin C - was discovered by the Italian doctor Giuseppe Brotzu of the University of Cagliari.
Over the years, numerous cephalosporins have been developed with increased activity compared to their natural precursor, thus obtaining more effective drugs with a broader spectrum of action.
Cephalosporins are also bactericidal antibiotics.
Cefazolin, cefalexin, cefuroxime, cefaclor, ceftriaxone, ceftazidime, cefixime and cefpodoxime belong to this class of drugs.
carbapenems
The progenitor of this class of drugs is thienamycin, which was isolated for the first time from actinomycete Streptomyces cattleya .
It was discovered that thienamycin was a compound with an intense antibacterial activity, with a broad spectrum of action and capable of inhibiting some types of β-lactamases (particular enzymes produced by some bacterial species able to hydrolyse beta-lactam and to inactivate the antibiotic).
Since thienamycin was found to be very unstable and difficult to isolate, changes were made to its structure, thus obtaining a more stable first semi-synthetic derivative, the imipenem.
Also included in this class of antibiotics is meropenem and œrapenem.
Carbapenems are bacteriostatic antibiotics, that is, they are not able to kill bacterial cells, but inhibit their growth.
monobactams
The only drug belonging to this class of antibiotics is aztreonam.
Aztreonam does not come from natural compounds, but is of completely synthetic origin. It has a spectrum of action restricted to Gram-negative bacteria and also has the ability to inactivate certain types of β-lactamases.
Action mechanism
All beta-lactam antibiotics act by interfering with the synthesis of the bacterial cell wall, ie they interfere with peptidoglycan synthesis.
Peptidoglycan is a polymer made up of parallel chains of nitrogenated carbohydrates, joined together by transverse bonds between amino acid residues.
These bonds are formed by particular enzymes belonging to the peptidase family (carboxypeptidase, transpeptidase and endopeptidase).
The beta-lactam antibiotics bind to these peptidases preventing the formation of the aforementioned cross-links; in this way, weak areas are formed inside the peptidoglycan that lead to the lysis and death of the bacterial cell.
Resistance to beta-lactam antibiotics
Some bacterial species are resistant to beta-lactam antibiotics because they synthesize particular enzymes ( β-lactamases ) able to hydrolyze the beta-lactam ring; doing so, they inactivate the antibiotic preventing it from performing its function.
To remedy this resistance problem, beta-lactam antibiotics can be administered together with other compounds called β-lactamase inhibitors which - as the name implies - inhibit the activity of these enzymes.
Examples of these inhibitors are clavulanic acid which is often found in association with amoxicillin (such as, for example, in the medicinal Clavulin®), sulbactam which is found in combination with ampicillin (such as, for example, in the Unasyn® medicine) and tazobactam which can be found in many medicines in combination with piperacillin (such as, for example, in the medicine Tazocin®).
However, antibiotic resistance is not only caused by the production of β-lactamase 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.
Unfortunately, the phenomenon of antibiotic resistance has greatly increased in recent years, mainly because of the abuse and the misuse that is done.
Therefore, drugs as powerful and effective as beta-lactams are increasingly likely to become useless due to the continuous development of resistant bacterial strains.
