Antimicrobial Chemotherapy

The aminoglycosides are a clinically important group of antibiotics that have a broad-spectrum of activity and that are bactericidal in action. The family includes streptomycin, gentamicin, tobramycin, kanamycin, amikacin and netilmicin. The aminocyclitols such as spectinomycin are closely related and have a similar mode of action. Aminoglycosides have a variety of effects within the bacterial cell but principally they inhibit protein synthesis by binding to the 30S ribosomal subunit to prevent the formation of an initiation complex with messenger RNA. They also cause misreading of the messenger RNA message, leading to the production of nonsense peptides. Another important function of the aminoglycosides is that they increase membrane leakage. Antibiotics such as gentamicin and kanamycin exist as mixtures of several closely related structural compounds; those like netilmicin and amikacin have a single molecular structure.

Chemical structure of streptomycin

Chemical structure of gentamicin

Chemical structure of spectinomycin

Aminoglycosides are toxic to humans, causing problems with kidney function and damage to the eighth cranial nerve. This leads to hearing loss and balance difficulties. The therapeutic use of the aminoglycosides requires careful monitoring to ensure adequate therapeutic levels are maintained, without the accumulation of the drug to toxic levels.

The tetracyclines are a family of antibiotics that have a four-ring structure. They are broad-spectrum agents that inhibit binding of the aminoacyl tRNA to the 30S ribosomal subunit in bacteria. The action is bacteriostatic and can therefore be reversed upon removal of the drug. The clinical use of tetracyclines is generally confined to adults. This is because tetracyclines affect bone development and can cause staining of teeth in children.

Chemical structure of a tetracycline

Tigecycline is a new tetracycline that is active against meticillin-resistant Staphylococcus aureus.

Chemical structure of tigecycline

The broad-spectrum bacteriostatic agent chloramphenicol is toxic to humans. It has been recognised as a cause of aplastic anaemia and so its use is confined to life-threatening infections where no alternative therapy is available. It acts by binding to the 50S ribosomal subunit and blocking the formation of the peptide bond by inhibiting peptidyl transferase activity. It is a potent inhibitor of mitochondrial protein synthesis in eukaryotic cells.

Chemical structure of chloramphenicol

The macrolides are a group of antibiotics that have a large, lactone ring structure. These may be 14- or 16-membered rings. The most widely used macrolides are erythromycin and clarithromycin. These are relatively non-toxic antibiotics, most active against Gram-positive bacteria. Erythromycin is, however, the treatment of choice for Legionnaire's disease caused by the Gram-negative bacillus Legionella pneumophila and it is also active against Haemophilus influenzae, another Gram-negative bacillus. Erythromycin binds to the 50S ribosomal subunit and inhibits either peptidyl transferase activity or translocation of the growing peptide. Newer macrolides include azithromycin and clarithromycin. These have the same activity as erythromycin but they have better pharmacological properties.

Chemical structure of erythromycin

Chemical structure of azithromycin

Chemical structure of a macrolide with a 16-membered ring

The lincosamide antibiotic lincomycin and its semi-synthetic derivative clindamycin have a similar mode of action.

Chemical structure of lincomycin

 

Chemical structure of clindamycin

The steroid antibiotic fusidic acid is used to treat Gram-positive infections. It acts by preventing translocation of peptidyl tRNA. Resistant mutants may easily be selected, even during therapy and therefore fusidic acid is usually administered in combination with another antibiotic. This helps reduce the risk of selecting resistant mutants. To survive, the fusidic acid resistant mutants must also become resistant to the antibiotic given in combination. If the chance of selecting fusidic acid resistance is 10^-5 and that of chromosomal mutation to resistance to the second agent is 10^-8 then the theoretical chance of a double mutant arising from combination therapy is 10^-13 (=10^-5 x 10^-8). This is so low as to be considered insignificant but, in practice, the chance of acquiring resistance to the second agent is increased by the presence of mobile bacterial genes encoding resistance. These can be acquired more easily than chromosomal genes can mutate to confer a resistance phenotype on a bacterium.

Chemical structure of fusidic acid

The streptogramins fall into two groups, A and B. Streptogramins belonging toGroup A have a large non-peptide ring, which is polyunsaturated. Streptogramins related to streptogramin B are cyclic peptides. They differ in their modes of action although both inhibit bacterial protein synthesis. Group A strptogramins distort the ribosome to prevent binding of the t-RNA; Group B streptogramins are thought to block translocation of the growing peptide.

Chemical structure of streptogramin A

 

Chemical structure of streptogramin B

A combination of dalfopristin and quinupristin has recently been introduced for use in the treatment of meticillin-resistant Staphylococcus aureus. Dalfopristin is a Type A streptogramin and quinupristin is a Type B streptogramin. In combination, these drugs show a synergistic effect.

Chemical structure of dalfopristin

Chemical structure of quintupristin

 

There is an analogue of iso-leucine: mupirocin. It inhibits the iso-leucyl-transfer RNA synthetase, thereby preventing the incorporation of iso-leucine into growing polypeptide chains. It is not toxic to humans but can only be used topically for skin infections. This is because humans rapidly metabolise the drug to an inactive form. Therefore, in systemic therapy it is destroyed before it can be effective.

Chemical structure of mupirocin

Linezolid is the first of a new class of bacterial protein synthesis inhibitors, the oxazolidinone antibiotics. Its mode of action is to prevent the initiation of protein synthesis. It does this by interfering with the interaction between mRNA and the two ribosomal subunits necessary for the initiation of translation of the messenger RNA into the nascent peptide chain. It is active against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus and vancomycin resistant enterococci.

Chemical structure of linezolid