AMINOGLYCOSIDES

 

Objectives of the topic:  By the end of this topic, the reader/medical student will be able to;

1.  Describe aminoglycoside as a class of antibiotics

2.  Identify some of the disease treated by aminoglycosides

Introduction:  The aminoglycosides include  streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others.  They are used most widely in combination with a β-lactam antibiotic in serious infections with gram-negative bacteria, in combination with vancomycin or a β-lactam antibiotic for gram-positive endocarditis, and for treatment of tuberculosis.  

General Properties of Aminoglycosides:  They are water-soluble, stable in solution, and more active at alkaline than at acid pH.  

Mechanism of Action:  The mode of action of streptomycin has been studied far more closely than that of other aminoglycosides, but they probably all act similarly. Aminoglycosides are irreversible inhibitors of protein synthesis, with bactericidal activity.  

Pharmacodynamics:  The initial event is passive diffusion via porin channels across the outer membrane.  Drug is then actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process.  The transmembrane electrochemical gradient supplies the energy for this process, and transport is coupled to a proton pump.  Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient.  Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin; this enhancement may be the basis of the synergism of these antibiotics with aminoglycosides.  

Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins.  Protein synthesis is inhibited by aminoglycosides in at least three ways:  

(1) interference with the initiation complex of peptide formation; 

(2) misreading of mRNA, which causes incorporation of incorrect amino acids into the peptide and results in a nonfunctional or toxic protein; and 

(3) breakup of polysomes into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irreversible and lethal for the cell.  

Mechanisms of Resistance:  Three principal mechanisms have been established: (1) production of a transferase enzyme or enzymes inactivates the aminoglycoside by adenylylation, acetylation, or phosphorylation.  This is the principal type of resistance encountered clinically.  

(2) There is impaired entry of aminoglycoside into the cell.  This may be genotypic, resulting from mutation or deletion of a porin protein or proteins involved in transport and maintenance of the electrochemical gradient; or phenotypic, such as, resulting from growth conditions under which the oxygen-dependent transport process described above is not functional.  

(3) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation.  

RELATED;

1.  QUINOLONES

2.  PENICILLINS

3.  ANTIMICROBIALDRUG RESISTANCE

4.  PHARMACOLOGY AND THERAPEUTICS

REFERENCES