All antibiotics have the common property of interfering in some way with a normal, critical function of the target bacterial cell. The most commonly used antibiotics exert their effect by one of the following methods:
1 Inhibition of cell wall synthesis (group I)
2 Disruption of cell membranes (group II)
3 Interference with protein synthesis (group III)
4 Interference with nucleic acid synthesis (group IV)
Table 14.2 lists examples of each group. Those antibiotics belonging to groups I and III are better able to discriminate between procaryotic and eucaryotic cells, and consequently show more selective toxicity and a higher therapeutic index.
Group I: Inhibitors of cell wall synthesis
The main group which work in this way are the j-lactam antibiotics, so-called because they contain a j-lactam ring in their structure. Included among this group are the penicillins and the cephalosporins. See also Box 14.4.
You may recall from our discussion of bacterial cell wall structure in Chapter 3 that an important factor in the strengthening of the peptidoglycan component of the bacterial cell walls is the cross-linking of chains by transpeptidation. It is this process which is acted on by the j -lactams; they bind irreversibly to the transpep-tidase enzyme, forming covalent bonds with a serine
The therapeutic index provides a measure of the selective toxicity of a chemotherapeu-tic agent. It is the ratio between the concentration at which the substance causes harm to its host (toxic dose) and that at which it is required to be clinically effective (therapeutic dose). It is therefore desirable for an antibiotic to have a high therapeutic index.
Table 14.2 Some commonly used antibiotic classes
Inhibitors of cell wall synthesis Disrupters of cell membranes Inhibitors of protein synthesis Inhibitors of nucleic acid synthesis
Penicillins, cephalosporins Polymixins, polyenes Streptomycin, tetracyclines Rifamycins residue within the enzyme's active site. The cell wall continues to form, but becomes progressively weaker as more new, unlinked, peptidoglycan is set down. Since bacteria are generally to be found in a hypotonic environment, as the wall weakens, water enters the cell, leading to swelling and then lysis.
Penicillins The first j-lactam antibiotic to be discovered was benzylpenicillin, or penicillin-G, whose action is restricted to Gram-positive bacteria, because it is unable to penetrate the Gram-negative cell wall. It is effective against Gram-positive bacteria when administered intramuscularly, but cannot be taken by mouth because it is broken down in the acid conditions of the stomach. Another naturally occurring penicillin, penicillin-V, represented an advance inasmuch as it is less acid-labile and can therefore be taken orally. All the penicillins are based on a core structure or nucleus called 6-amino-penicillanic acid (Figure 14.2); extensive research has led to the development of many variants of this, the so-called semisynthetic penicillins. These have attached to their nucleus novel side chains not encountered in nature, and have overcome some of the problems inherent in naturally occurring penicillins such as instability and narrow specificity (Figure 14.3).
Ampicillin is a semi-synthetic penicillin that has a broader specificity (Box 14.5) than Penicillin G; it is appreciably more effective against Gram-negative bacteria such as Salmonella and E. coli, its hydrophobic nature making it better able to penetrate their outer membrane. It has the additional benefit of being acid-stable and can therefore be taken orally.
Another drawback to natural penicillins is that they are susceptible to naturally occurring bacterial j-lactamases (also called penicillinases), which breaks a bond in the j-lactam core of the penicillin molecule (Figure 14.4). Sometimes, j-lactam antibiotics
Semisynthetic penicillins are based on the core structure of the naturally occurring molecule, with the addition of chemically synthesized side chains.
Box 14.4 j-lactam antibiotics have a second mode of action
The j-lactams also act by preventing the natural regulation of enzymes called au-tolysins. These enzymes function by breaking down peptidoglycan in a controlled fashion, causing breaks to allow for the addition of new peptidoglycan as the cell grows, and are normally regulated by naturally occurring inhibitors. The j-lactams neutralise the activity of these inhibitors, leading to further breakdown of the cell wall.
Box 14.5 Broad spectrum or narrow spectrum?
Certain antibiotics, due to the mechanism of their action, are only effective against a few different pathogens, while others can be used successfully against many different kinds. They are said to have, respectively, a narrow spectrum and a broad spectrum of activity.
On the face of it, all things being equal, you would expect your doctor to choose the antibiotic with the broadest possible spectrum of activity, but this isn't always the wisest option. When the cause of an infection isn't known, it makes sense to hedge one's bets and prescribe a broad-spectrum antibiotic ('whatever it is, this should sort it!'), but this policy is not without its dangers. The drug is likely to kill off many of the host's own resident microflora, which can lead to a superinfection, and the development of antibiotic-resistant strains is also made more likely. If the identity of the pathogen is suspected, an appropriate narrow-spectrum drug is to be preferred.
are taken in combination with a j -lactamase inhibitor such as clavulanic acid. This binds to the j-lactamase with a high affinity, preventing it from acting on the antibiotic. Some semisynthetic penicillins such as methicillin and oxacillin are resistant to attack by the j -lactamases that can render certain bacteria resistant to their naturally occurring forms.
Penicillin is not an appropriate treatment for the estimated 1-5 per cent of adults who show an allergic reaction to it; in extreme cases, death from anaphylactic shock can result.
Cephalosporins The cephalosporins, like the penicillins, have a structure based on a ß-lactam ring (Figure 14.5). They also exert their effect on transpeptidases, but generally have a broader specificity and are more resistant to the action of ß-lactamases. Ceftriaxone, for example, is now used in the treatment of gonorrhoeal infections, caused by penicillin-resistant strains of Neisseria gonorrhoeae. In addition, patients who are allergic to penicillin are often treated with cephalosporins. Cephalosporins were first
An anaphylactic shock is an extreme form of hy-persensitivity reaction.
Figure 14.4 Action of f-lactamase on penicillin. A number of bacteria, especially staphylococci, possess the enzyme f -lactamase (penicillinase), which inactivates penicillin by cleavage of the f -lactam ring at the point marked by the arrow
Figure 14.5 Cepahalosporins are based on a nucleus of 7-amino-cephalosoranic acid, which, like the penicillins, features a f-lactam ring (shown as a square). Note that each molecule has two variable side chains isolated in the late 1940s from a marine fungus called Cephalosporium acremonium, and came into general use in the 1960s. So-called second, third and fourth generation cephalosporins have been developed to widen the spectrum of activity to include many Gram-negative organisms, and to keep one step ahead of pathogens developing resistance to earlier versions.
Both penicillins and cephalosporins are also used prophylactically, that is, in the prevention of infections, prior to surgery in particularly vulnerable patients.
Other antibiotics that affect the cell wall Carbapenems are f -lactam antibiotics produced naturally by a species of Streptomyces. A semisynthetic form, imipenem, is active against a wide range of Gram-positive and -negative bacteria, and is used when resistance to other f -lactams has developed.
Bacitracin and vancomycin are two other antibiotics that exert their effect on the cell wall, but by a different mechanism. Bacitracin is derived from species of Bacillus and acts on bactoprenol pyrophosphate, the lipid carrier molecule responsible for transporting units of peptidoglycan across the cell membrane to their site of incorporation into the cell wall (see Chapter 3). Its use is restricted to topical (surface) application, since its use internally can cause kidney damage. Vancomycin is a highly toxic antibiotic with a narrow spectrum of use against Gram-positive organisms such as streptococci and staphylococci. It is particularly important in its use against infections caused by organisms resistant to methicillin and the cephalosporins, such as methicillin-resistant Staphylococcus aureus (MRSA) (see Resistance to Antibiotics below). It is not absorbed from the gastrointestinal tract and is therefore most commonly administered intravenously.
Group II: Antibiotics that disrupt cell membranes
Polymixins are a class of antibiotic that act by disrupting the phospholipids of the cytoplasmic membrane and causing leakage of cell contents. Produced naturally by a species of Bacillus, polymixins are effective against pseudomonad infections of wounds and burns, often in combination with bacitracin and neomycin (an inhibitor of protein synthesis; see below). Their toxicity makes them unsuitable for internal use. Polyene antibiotics such as amphotericin and nystatin are antifungal agents that act on the sterol components of membranes; they are discussed more fully towards the end of this chapter.
Group III: Inhibitors of protein synthesis
Antibiotics that act by affecting protein synthesis generally have a relatively broad spectrum of action. As we saw in our historical review earlier in this chapter, streptomycin was the first antibiotic that was shown to be effective against Gram-negative organisms. Its discovery in 1943 was particularly welcome since such organisms were unaffected by penicillin or sulphonamides. It proved to be particularly useful in the treatment of tuberculosis, the causative agent of which, Mycobacterium tuberculosis, is protected against the effects of penicillin by the waxy layer of mycolic acids in its cell wall.
Streptomycin belongs to a group of antibiotics called aminoglycosides, which act by binding to the 30S subunit of the bacterial ribosome, preventing attachment of the 50S subunit to the initiation complex (Figure 14.6). They can thus discriminate between procaryotic (70S) and eucaryotic (80S) ribosomes, and consequently have a relatively high therapeutic index (although not as high as cell wall inhibitors). Other members of this group are gentamicin, kanamycin and neomycin. Like some other 'wonder drugs', streptomycin has proved to have undesirable side-effects; these have led to it being replaced in most applications by safer alternatives. In addition, bacterial resistance to streptomycin is widespread, further diminishing its usefulness. Use of the
Figure 14.6 Inhibitors of protein synthesis. (a) By binding to the 30S subunit of the bacterial ribosome, aminoglycosides block the attachment of the 50S subunit. This prevents completion of the initiation complex, thus protein synthesis is inhibited. (b) Tetracyclines distort the shape of the 30S subunit, preventing the attachment of the appropriate amino-acyl tRNA. (c) Chloramphenicol inhibits peptidyltransferase and prevents formation of new peptide bonds. (d) Macrolides such as erythromycin bind to the 50S subunit, preventing elongation of the growing peptide chain
Figure 14.6 Inhibitors of protein synthesis. (a) By binding to the 30S subunit of the bacterial ribosome, aminoglycosides block the attachment of the 50S subunit. This prevents completion of the initiation complex, thus protein synthesis is inhibited. (b) Tetracyclines distort the shape of the 30S subunit, preventing the attachment of the appropriate amino-acyl tRNA. (c) Chloramphenicol inhibits peptidyltransferase and prevents formation of new peptide bonds. (d) Macrolides such as erythromycin bind to the 50S subunit, preventing elongation of the growing peptide chain aminoglycosides as a group has diminished since the development of later generation cephalosporins and the tetracyclines.
Tetracyclines also work by binding to the 30S ribosomal subunit, preventing the attachment of aminoacyl tRNA, and therefore extension of the peptide chain (Figure 14.6). They are yet another group of antibiotics produced by Streptomyces spp. Both natural and semisynthetic tetracyclines are easily absorbed from the intestine, allowing them to be taken orally. Coupled with their broad specificity (the broadest of any antibiotic), this led to inappropriately widespread use in the years following their discovery, sometimes resulting in complications caused by the destruction of the normal resident microflora. Tetracyclines are still used for a number of applications, notably to treat a variety of sexually transmitted diseases.
Two important antibiotics which act on the larger, 50S, subunit of the procaryotic ribosome are erythromycin and chloramphenicol. Both combine with the subunit in such a way as to prevent the assembly of amino acids into a chain (Figure 14.6). Chloramphenicol was the first antibiotic to be discovered with a broad spectrum of activity; it also derives originally from Streptomyces spp., but is nowadays produced synthetically. Its use has become severely restricted since it was shown to have some serious side-effects, notably on the bone marrow, but it remains the agent of choice for the treatment of typhoid fever.
Erythromycin is the best known of the macrolide group of antibiotics. Unlike chlo-ramphenicol, it has a large hydrophobic molecule and is unable to gain access to most Gram-negative bacteria, thus restricting its spectrum of activity. Erythromycin can be taken orally and has a similar spectrum of activity to penicillin G; it is often used instead of penicillin in the treatment of staphylococcal and streptococcal infections in children. It is particularly appropriate for this application as it is one of the least toxic of all commonly used antibiotics.
Group IV: Inhibitors of nucleic acid synthesis
Rifampin belongs to a group of agents called rifamycins. It acts by inhibiting the enzyme RNA polymerase, thereby preventing the production of mRNA. Rifampin is used against the mycobacteria that cause tuberculosis, an application for which its ability to penetrate tissues makes it well suited. Unlike most antibiotics, rifampin interacts with other drugs, often reducing or nullifying their effect. When used in high doses, it has the unusual side-effect of turning secretions such as tears, sweat and saliva, as well as the skin, an orangered colour. As we have already seen, the quinolone group of synthetic antimicrobial drugs act by disrupting DNA replication.
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