Aminoglycosides, "Polybasic amino groups linked glycosidically (sugar - O - sugar) to two or more amino sugar residues. For example, In Streptomycin, Streptidine (an ploybasic amino group) linked glycosidically to streptose & N-methyl-L-glucosamine (amino sugars).History
- Streptomycin - 1st member discovered in 1944 by Waksman and his colleagues.
Classification
Systemic Aminoglycosides
Streptomycin | Amikacin | Gentamicin | Sisomicin | Kanamycin | Netilmicin | Tobramycin | Paromomycin
Topical Aminoglycosides
Neomycin and Framycetin
Mechanism of action
Aminoglycosides binds to several sites at 30S and 50S subunits. The antimicrobial action is produced through three mechanism -
Freeze initiation of protein synthesis
Prevents polysome formation.
Binding of aminoglycosides cause distortion of mRNA codon recognition resulting in misreading of the code (wrong amino acids are produced)
Uses
Tuberculosis
Sub acute bacterial endocarditis
Plague
Tularemia
Adverse Effects
- Ototoxicity (Cochlear damage, Vestibular damage)
- Nephrotoxicity
- Neuromuscular blockade
Structure Activity Relationship
In aminoglycosides, 2 or more amino sugars joined in glycoside linkage to a highly substituted 1,3-diaminocyclo hexane, which is a centrally placed ring.
Streptomycin - amino sugars are attached to STREPTIDINE whereas in all other aminoglycosides, two amino sugars are attached to 2-deoxy streptamine.
i. Amino sugar portion
Bacterial inactivating enzymes targets C-6 and C-2 position. Substitution with methyl group at C-6 increases the enzyme resistance.
Cleavage of 3-hydroxyl or the 4-hydroxyl or both groups does not affect the activity.
ii. Centrally placed hexose ring
Acylation and Ethylation of C-1 amino group does not increase the activity. But helps to retain the antibacterial property.
2-hydroxylation and 5-deoxygenation result in the increased inhibition of bacterial inactivating enzyme systems. e.g.: Sisomicin
