Aminoglycosides

(Antibacterial agents that inhibit protein synthesis)(Antibiotics)

-These are antibiotics obtained from the genus Streptomyces
-The first aminoglycoside antibiotic used = streptomycin {lead compound} Prototype
Mechanism of Action:
* Aminoglycosides apparently bind initially to external lipopolysaccharides and
diffuse into the cells in small amount
* The aminoglycosides are bactericidal due to a combination of toxic effects.
* At less than toxic doses, they bind to the 16S ribosomal DNA portion of the
30S ribosomal subparticle impairing the proofreading function of the ribosome.
This leads to mistranslation of RNA templates and the consequent selection of
wrong amino acids and formation of so-called nonsense proteins-non-functional protein
Therapeutic application:
-aminoglycosides have broad antibiotic spectra against aerobic Gram (+) and
Gram (-) bacteria
- However, they are reserved for serious infections caused by Gram (-)
organisms because of serious toxicities which are often delayed in onset.
-Streptomycin is most commonly used for the treatment of tuberculosis
-Spectinomycin for treatment of gonorrhea.
Toxicity:
-These agents have intrinsically broad antimicrobial spectra but their toxicity
potential limits their clinical use to severe infections by Gram (-) bacteria.
a) totoxicity to functions mediated by the eighth cranial nerve, such as
hearing loss and vertigo.
b) kidney tubular necrosis producing decrease in glomerular function.
-These toxic effects are apparently mediated by the special affinity of these
aminoglycosides to kidney cells and to the sensory cells of the inner ear
General properties
1) Very poorly absorbed from GIT [highly polar compounds]  when used orally
it's intended for local GIT infections. But given I.M. for systemic infections
2) excreted in their active form in fairly high concentrations in the urine
following injection,so when the kidney is not functionalized we must reduce
the dose to avoid the toxic effect
3) They are basic and form acid addition salts
4) They are more commonly given intramuscularly or by perfusion
Chemical properties
• Pharmacophoric unit is 1,3-diamino Inositol moiety “aminocyclitol unit”.
• From this moiety ; we have 3 pharmacophoric groups :

-Several of the alcoholic functions of the 1,3-diaminoinositol are substituted

through glycosidic bonds with characteristic aminosugars to form pseudo-
oligosaccharides.
Bacterial Resistance:
1) Production of aminoglycoside modifying enzymes: Several of the
aminoglycoside antibiotics can be inactivated by enzymes which occur in gram-
negative bacteria carrying R-factors.
R-factor genes mediated the formation of aminoglycoside-inactivating
enzymes
-Aminoglycoside 6'-N-acetyltransferase:
enzymes make acetylation of NH2 group. (ANT)
-O-Phosphoryl transferase: enzymes make
phosphorylation of OH group. (APT) only for
aminoglycoside having 3' OH
- O-Adenyl transferase : enzymes make O-adenylation. (AAT)
2) Permeability defect, lead to decrease the uptake of aminoglycoside into
bacterial cells.
Classification of aminoglycosides
1. Aminoglycosides containing streptidine e.g. streptomycin
2. Aminoglycosides containing 2-deoxystreptamine e.g. kanamycin, tobramycin,
gentamycin, neomycin, and amikacin.
3. Aminoglycosides containing spectinamine e.g. spectinomycin
 [I] Aminoglycosides containing Streptidine
Streptomycin
OH NH-CH3
HO H2N
O NH
HOH2C HN

O OH
O
N-methyl glucosamine NH NH2
[amino sugar] HO OH
CH3 HO NH
O
OHC
Streptidine
-CH2-OH
[Pharmacophore]
L-Streptose
Dihydro Streptomycin
[neutral sugar]

Streptobiosamine
[Disaccharide]
-Resistance to streptomycin takes the now familiar course of N-acetylation,
O-phosphorylation and O-adenylation of specific functional groups in the
streptomycin molecule
-Streptomycin is useful also against bubonic plague, leprosy, and tularemia.
-hydrophilic nature  poorly absorbed from GIT [usually taken I.M.]
-Introduced primarily for treatment of T.B.[ may be due to presence of two
guanido moieties]. But replaced now by other antibiotics as Rifampin.
[ii] Aminoglycosides containing 2-deoxy Streptamine