This document summarizes key structural activity relationships of aminoglycoside antibiotics. It notes that ring I is important for broad spectrum activity but is also the major site of inactivation by aminoglycoside modifying enzymes. The amino groups at positions 6' and 2' on ring I are particularly important for activity. Phosphorylation of the 3'OH on ring I reduces binding to the 30S ribosomal subunit. Methylation of the 6' carbon or amino group confers resistance to enzymatic acetylation of the 6' amino group without reducing antibacterial potency. Removal of the 3' or 4' hydroxyl, as seen in kanamycin B or dibekacin, does not reduce potency

1. Chemistry & SAR (Structural activity relationship) of Aminoglycosides
 Ring I
is important for broad spectrum in activity, at the same time it is the major site for enzymatic
inactivation by AAC and APH.
 Amino group at 6΄ and 2΄ are important (Kanamycin B> A>C).
6’amino, 2’amino > 6’amino, 2’hydroxyl > 6’hydroxyl, 2’amino
 Phosphorylation of 3΄OH will reduce the binding to ribosomes 30S subunit.
Methylation at either 6’ carbon or 6’ amino-confers resistance to enzymatic acetylation of the
6’ amino group and doesn’t lower antibacterial activity
Removal of 3’ hydroxyl or 4’ hydroxyl -
Kanamycin B or dibekacin
does’nt reduce antibacterial potency
Lack of Oxygen function at 3’ or 4’ along with presence of 4’,5’ double bond
Gentamicins, sisomicin and netilamicin
No inactivation by phosphotransferase as this enzyme phoshorelates at 3’ OH group
 Ring II
o can accept few structural modifications and retaining the same activity: example is the
acetylation of the amino group at position-1 (amikacin).
o can be ribose, streptose (five memeberd ring) or streptamine (six memeberd ring).
 Ring III
less sensitive to structural changes but the amino group at position 3΄΄ can be 1° or 2° for
maximum activity.
RESISTANCE
AG inactivating enzymes includes- AAC, APH & ANT
AAC-Aminoacyl transferase-acetylates
2’-NH2 of the ring I / 6’NH2 of the ring I/ 3-NH2 of the ring II
APH- Phosphotransferase-phosphorylates
3’OH of the ring I/ 2” OH of the ring III and
ANT-nucelotidyltransferases- adenylates
2” OH of the ring III /`4’ OH of the ring III or ring I