Aminoglycosides and streptomycin- pharmaceutical Chemistry

1. AMINOGLYCOSIDES
AND STREPTOMYCIN
Humna Mehmood
BS CHEMISTRY
Session: 2017-2021
GPCSF

2. INTRODUCTION
• Bactericidal antibiotics
• Source: Actinomycetes and some are semisynthetic
• Streptomycin, the first aminoglycoside
• kanamycin, neomycin, paromomycin, gentamicin, tobramycin,
and netilmicin etc.
• Suffix is different because of source
• -Mycin: Streptomyces
• -Micin: Micromonospora

3. CHEMISTRY
Aminoglycosides are so named because their structures consist of
amino sugars linked glycosidically.
• All have at least one aminohexose, and some have a pentose
lacking an amino group.
• In each clinically useful aminoglycosides: a highly substituted
1,3-diaminocyclohexane central ring present
 In streptomycin, it is streptadine.
 In kanamycin, neomycin, gentamicin, and tobramycin, it is
deoxystreptamine.

4. CHEMISTRY
• Streptomycin
Molecular formula: C21H39N7O12
• Tobramycin
Molecular formula: C18H39N5O13S
• Knamycin
Molecular formula: C18H38N4O15S

5. CHEMICAL PROPERTIES
• Strongly basic compounds that exist as poly cations at
physiological PH.
• Their inorganic acid salts are very soluble in water.
• The high water solubility of the aminoglycosides no doubt
contributes to their pharmacokinetic properties (what body do
to drugs).

6. SPECTRUM OF ACTIVITY
• Broad spectrum antibiotics
• Greatest usefulness lies in the treatment of serious
systemic infections caused by aerobic Gram-negative
bacilli.
• Anaerobic bacteria are invariably resistant to the
aminoglycosides. Oxygen is required to cross cell
membrane of bacteria.
• Streptomycin: chemotherapy of TB, brucellosis,
tularemia, and Yersinia infections.
• Paromomycin: primarily used in the chemotherapy of
amebic dysentery.

7. Mechanism of Action
• Initially, aminoglycosides penetrate bacterial cell wall to reach
periplasmic space through porin channels(passive diffusion)
• Further transport across cytoplasmic membrane takes place by
active transport by proton pump; an oxygen dependent process.
• All are more active at alkaline pH than acidic.

8. Mechanism of Action
• Act directly on the bacterial ribosome to inhibit the
initiation of protein synthesis and to interfere with the
fidelity of translation of the genetic message.
• Bind to the 30S ribosomal subunit to form a complex
that cannot initiate proper amino acid polymerization.

10. How bactericidal?
• Cidal action is due to secondary action in te bacteriacl
cell membrane.
• After exposure to aminoglycoside, bacteria become
more permeable to ions, amino acids and even
proteins leak out followed by cell death.

11. Post antibiotic effect
• Residual bactericidal effect persist even after serum
concentration has fallen below minimum inhibitory
concentration.
• Single daily dose is as effective as multiple dosing
• less toxic
• Less renal accumulation, less toxic

12. MECHANISM OF RESISTANT
• Three types of mechanisms:
• Synthesis of plasmid mediated bacterial transferase
enzymes that can inactivate aminoglycosides.
• Mutation/deletion of porin channels resulting in
decreased transport of aminoglycoside into the bacterial
cytosol.
• By deletion or alteration of the receptor protein on 30S
(Target) ribosomal unit because of mutations.
Attachment of drug with 30S ribosomal unit is thus
prevented.

13. PHARMACOKINETICS
WHAT DO BODY DO TO DRUG?
• Highly polar drugs
• Given I.V. (intravenous; into the vein) or I.M.
(intramuscular)
– Rapid absorption from i.m. sites.
• They distribute well into most body fluids but not into the
central nervous system, bone, or fatty or connective tissues.
• They tend to concentrate in the kidneys and are excreted by
glomerular filtration.
• Aminoglycosides are apparently not metabolized in vivo
(within the body)
• Excreted through kidney.

14. TOXICITY/ADVERSE EFFECTS
• Ototoxicity
• Cochlear toxicity
– Result in hearing loss
– Cochlear toxicity is more with
neomycin & amikacin.
• Vestibular toxicity
– Result in hearing balance
– Vestibular toxicity is more with
Streptomycin & Gentamycin
• Old patients more susceptible.

15. TOXICITY/ADVERSE EFFECTS
• Nephrotoxicity
• Manifests as tubular damage resulting
in
– loss of urinary concentrating power
– nitrogen retention
• neomycin, gentamicin, amikacin and
tobramycin are more nephrotoxic than
streptomycin.
• 10-15% of all renal failure cases.

16. TOXICITY/ADVERSE EFFECTS
Neuromuscular blockade
• drugs interfere with calcium ions
movements through the calcium
channels of the membrane of
the motor nerve-endings and inhibit acetylcholine
release at the synaptic cleft.
• Reduce postsynaptic senstivity to the transmitter
• Association with anaesthesia

17. STREPTOMYCIN
• Streptomycin, the first aminoglycoside
• Was the result of a planned and deliberate search from 1939 to
1944 by schwatz and associates.
• Discovered in 1943
• Obtained from streptomyces gresius
• works by blocking the ability of 30S ribosomal subunits to make
proteins, which results in bacterial death

18. STREPTOMYCIN

19. STREPTOMYCIN
Synthesis
• Streptomycin is directly derived from glucose. Though the enzymes involved in
the synthesis of N-methyl glucosamine are not yet known, it is expected that
about 28 enzymes take part in the conversion of glucose into streptomycin.

20. STREPTOMYCIN
Use:
• Streptomycin is an antibiotic medication used to treat a
number of bacterial infections.This includes
• Tuberculosis,
• Endocarditis,
• Brucellosis,
• Burkholderia Infection,
• Plague
• Tularemia (Rat Bite Fever)
• For active tuberculosis it is often given together with drugs.
• It is given by injection into a vein or muscle.

21. STREPTOMYCIN
Use:
– Streptomycin controls bacterial diseases of certain fruit,
vegetables, seed, and ornamental crops.
– A major use is in the control of fireblight on apple and pear
trees.
• Cell culture
Streptomycin, in combination with penicillin, is used in a
standard antibiotic cocktail to prevent bacterial infection in cell
culture.
• Protein purification
When purifying protein from a biological extract, streptomycin
sulfate is sometimes added for removing nucleic acids

22. STREPTOMYCIN
Side effects:
• Vertigo (a condition where a person has the sensation of
moving or of surrounding objects moving when they are not)
• Ear toxicity
• Vomiting, numbness of the face, fever, and rash.
• Kidney toxicity, and can potentially interfere with diagnosis of
kidney malfunction.
• Use during pregnancy may result in permanent deafness in the
developing baby. Use appears to be safe while breastfeeding.
• It is not recommended in people with myasthenia gravis or
other neuromuscular disorders.