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WELCOME
OVERVIEW OF
AMINOGLYCOSIDES AND
OTHER PROTEIN SYNTHESIS
INHIBITORS
Presented By
Maruf Kamal (2008-3-70-006)
Sabbir Ahmed (2008-3-70-007)
Md. Tanvir Rahman (2009-1-70-018)
Introducton:
 An aminoglycoside is a molecule or a portion of a
molecule composed of amino-modified sugars.
 Several aminoglycosides function as antibiotics
that are effective against certain types of bacteria.
They include amikacin, arbekacin, gentamicin,
kanamycin, neomycin, netilmicin, paromomycin,
rhodostreptomycin, streptomycin, tobramycin,
and apramycin.
History:
Aminoglycoside
Year
Source organism
streptomycin
1944
Streptomyces griseus
neomycin
1949
Streptomyces fradiae
kanamycin
1957
Streptomyces kanamyceticus
paromomycin
1959
Streptomyces rimosus
spectinomycin
1962
Streptomyces spectabilis
gentamicin
1963
Micromonospora purpurea
tobramycin
1968
Streptomyces tenebrarius
sisomicin
1972
Micromonospora inyoensis
amikacin
1972
semisynthetic derivative of
kanamycin
netilmicin
1975
semisynthetic derivative of
sisomicin
History:
 The first aminoglycoside, streptomycin, was isolated
from Streptomyces griseus in 1943. Neomycin, isolated
from Streptomyces fradiae, had better activity than
streptomycin against aerobic gram-negative bacilli
but, because of its formidable toxicity, could not safely
be used systemically. Gentamicin, isolated from
Micromonospora in 1963, was a breakthrough in the
treatment of gram-negative bacillary infections,
including those caused by Pseudomonas aeruginosa.
Other aminoglycosides were subsequently developed,
including amikacin (Amikin), netilmicin
(Netromycin) and tobramycin (Nebcin), which are all
currently available for systemic use
Nomenclature
 Aminoglycosides that are derived from bacteria of the
Streptomyces genus are named with the suffix -mycin,
whereas those that are derived from Micromonospora
are named with the suffix -micin.
 This nomenclature system is not specific for
aminoglycosides. For example, vancomycin is a
glycopeptide antibiotic and erythromycin, which is
produced from the species Saccharopolyspora
erythraea (previously misclassified as Streptomyces)
along with its synthetic derivatives clarithromycin and
azithromycin, is a macrolide. All differ in their
mechanisms of action, however.
Physical and chemical properties:
 They are water-soluble due to their polar groups
(hydroxyl and amine groups), stable in solution
and more active at alkaline than at acid PH.
 Aminoglycosides frequently exhibit synergism
with β-lactams or vancomycin.
 However, aminoglycosides may complex with β-
lactam drugs, resulting in loss of activity and they
should not be mixed together for administration.
Specific Agents
 Amikacin (Amikin®),
 Gentamicin (Garamycin®),
 Kanamycin (Kantrex®),
 Neomycin, Netilmicin (Netromycin®),
 Streptomycin, Tobramycin (Nebcin®)
Structure of Aminoglycosides
Mechanism of action
 bactericidal; aminoglycosides bind to the 30S
subunit of the bacterial ribosome, interfering with
the binding of fMet-tRNA and therefore the
formation of the initiation complex. Binding to the
30S subunit may also cause misreading of mRNA
codons
 β-lactams, vancomycin facilitate uptake by Grampositive organisms
 resistance: via plasmid-mediated aminoglycosidemodifying enzymes
Mechanism of action
Pharmacokinetics
 poor oral absorption
 volume of distribution approximates the extracellular





space (about 0.26 L/kg)
(larger in cystic fibrosis patients, about 0.35 L/kg)
tissue distribution variable (poor CNS penetration)
negligible metabolism
renally eliminated (filtered, with a small amount of
proximal reabsorption)
elimination half-life: 2-3 hours (if renal function
normal)
Pharmacodynamics
 concentration-dependent killing
 postantibiotic effect (concentration-dependent)
SARs of Aminoglycosides
 Crucial for broad
spectrum activity
 Primary target for
inactivating enzymes
 Congeners with amino
groups at 2' and 6' are
especially active
SARs of Aminoglycosides
 Methylation of these
amines does not alter
activity,decreases
inactivation
 Hydroxyls at the 3' or 4‘
position are not
critically important
SARs of Aminoglycosides
 Modifications
compromise
antibacterial activity
 One exception is
amikacin with its
aminohydroxybutyrate
SARs of Aminoglycosides
 Substitution pattern is
somewhat more
flexible
 Only real requirement
is the amine at the 3"
position.
Spectrum of activity
 Aminoglycosides are classified as broad-spectrum
antibiotics, they used for treatment of serious
systemic infections caused by
 Aerobic Gm –ve bacilli.
 Aerobic Gm –ve and Gm +ve cocci (with the
exception of Staphylococci) tend to be less
sensitive to aminoglycosides and thus the β-lactam
and other antibiotics tend to be preferred for the
treatment of infections caused by these organisms.
Spectrum of activity
 broad gram-negative spectrum including P.




aeruginosa
gram-positive: synergistic in combination with ßlactams, glycopeptides
anaerobes: negligible activity
amikacin: Nocardia, MAI, certain rapid-growing
mycobacteria, gentamicin-resistant gram-negative
bacilli
streptomycin: multidrug-resistant tuberculosis,
tularemia, plague
Adverse reactions
 nephrotoxicity
 proximal acute tubular necrosis (ATN) → ↓ GFR
 likely related to inhibition of intracellular
phospholipases in the proximal tubule
 tends to be reversible
 associated factors: hypotension, dehydration,
duration of therapy, concomitant liver disease,
advanced age, other nephrotoxins (vancomycin)
 nephrotoxicity correlates with drug accumulation
in the renal cortex
Aminoglycoside accumulation in critically ill
surgical patients
Toxicity
 1- Nephrotoxicity
 2- Ototoxicity
 3- Neurotoxicity
 4- Neuromuscular blockade
 Additional adverse reactions with administration
of aminoglycosides may include: nausea,
vomiting, anorexia, rash, and urticaria.
Toxicity
 ototoxicity
 vestibulotoxic and cochleotoxic
 generally irreversible
 difficult to assess
 high tone frequencies affected first
 neuromuscular blockade
 rare but potentially serious
 enhanced by conditions or drugs affecting the NM
junction (e.g., myasthenia gravis, succinylcholine)
 can be treated with calcium
Contraindications:
 Aminoglycosides should not be given to patients requiring
long term therapy because of the potential for ototoxicity
and nephrotoxicity.
 These drugs are contraindicated in patients with:
- Preexisting hearing loss
- Myasthenia gravis
- Parkinsonism
- During lactation or pregnancy.
 The aminoglycosides are used cautiously in patients with
renal failure, in the elderly and in patients with
neuromuscular disorders.
Drug interactions:
 Administration of aminoglycosides with the
cephalosporins may increase the risk of
nephrotoxicity.
 When the aminoglycosides are administered with
loop diuretics there is an increase the risk of
ototoxicity (irreversible hearing loss).
 There is an increased risk of neuromuscular blockage
(paralysis of the respiratory muscles) if the
aminoglycosides are given shortly after general
anesthetic (neuromuscular junction blockers).
Drug interactions:
 Increased risk of nephrotoxicity and ototoxicity
when aminoglycosides given with vancomycin.
 Increased risk of nephrotoxicity when
aminoglycosides given with colistin.
 Aminoglycosides antagonize effects of
neostigmine.
Streptomycin sulfate
NH
H2N
NH
HO
OH
Streptidine
OH
NH
H2N
O
O
CHO
NH
L-Streptose
CH3
OH
O
HO
HO
O
NHCH3
N-Methyl-L- Glucosamine
OH
Streptomycin
Neomycin sulfate
Neosamine C
CH2NH2
6
5
O
1 NH2
2
3
4
6
1 NH2
HO
NH2 O
5
OH
5
Deoxystreptamine
CH2OH
O
6
O
CH2NH2
4
1
5
HO
O
3 2
1
3
HO
NH2 O
OH
Neosamine C
D-Ribose
HO
3
Neomycin C
Kanamycin sulfate
6`
Ring I
CH2R1
5`
HO
O
Ring II
1` NH2
2
3
4
6
1
O
5
O
HO
3`
HO
R2
HOCH 2
5``
HO 4``
H2 N
NH2
1``
OH
O
2``
Ring III
Kanamycin A R1=NH2, R2=OH
Kanamycin B R1=NH2, R2=NH2
Kanamycin C
R1=OH,
R2=NH2
Amikacin
Ring I
CH2NH2
6`
5` O
HO
3`
HO
Ring II
1` NH2
2
3
4
6
1
OH O
5
O
HO
HOCH 2
5``
HO 4``
H2N
O
1``
OH
2``
Ring III
Amikacin
O OH
NH-C-C-CH 2CH2NH2
H
Gentamicin sulfate
Netilmicin sulfate
6`
CH 2OH
5`
4`
Ring I
2`
3`
O
NH2
1`
H2 N
3
4
O
6
2 Ring II
1 NHR
5
O
HO
5``
CH3
4``
3``
O
1``
OH Ring III
2``
NHCH 3
OH
Sisomicin R= H
Netilmicin R= C2H5
Other Protein Synthesis Inhibitors
 Tetracycline
 Chloramphenicol
 Macrolides
 Mupirocin
 Quinolones
Mechanisms action of tetracycline
Commercially available tetracyclines
 First generation (Dose intervals shorter)
Chlorotetracycline
Oxytetracycline
Tetracycline
Dmeclocycline
• Second Generation (Dose interval longer)
Minocycline
Methacycline
Doxycycline
• Third Generation
Glycylcycline
 Mechanism action of chloramphenicol
Structure of cloramphenicol
MUPIROCIN
 Mupirocin is active against many gram-positive and
selected gram-negative bacteria. It has good activity
against S. pyogenes and methicillin-susceptible and
methicillin-resistant strains of S. aureus. It is
bactericidal at concentrations achieved with topical
application.
 Mupirocin inhibits bacterial protein synthesis by
reversible inhibition of Ile tRNA synthase. There is no
cross-resistance with other antibiotic classes. Clinically
insignificant, low-level resistance results from mutations
of the gene encoding Ile tRNA synthase or an extra
chromosomal copy of a gene encoding a modified Ile
tRNA synthase. High-level resistance is mediated by a
plasmid or chromosomal copy of a gene encoding a
“bypass” synthetase that binds Mupirocin poorly.
 Mechanism action of chloramphenicol
Structure of chloramphenicol
Mode of action of Macrolides
Examples of Macrolides
 Erythromycin
 Clarithromycin
 Roxithromycin
 Azithromycin
 Mupirocin is available as a 2% cream or ointment for
dermatologic use and as a 2% ointment for intranasal use.
The dermatological preparations are indicated for treatment
of traumatic skin lesions and impetigo secondarily infected
with S. aureus or S. pyogenes. Systemic absorption through
intact skin or skin lesions is minimal. Any Mupirocin
absorbed is rapidly metabolized to inactive monic acid.
 Mupirocin is effective in eradicating S. aureus carriage. The
consensus is that patients who may benefit from Mupirocin
prophylaxis are those with proven S. aureus nasal
colonization plus risk factors for distant infection or a
history of skin or soft tissue infections.
 Mupirocin may cause irritation and sensitization and contact
with the eyes should be avoided.
 Systemic reactions to Mupirocin occur rarely, if at all.
Application of the ointment to large surface areas should be
avoided in patients with renal failure to avoid accumulation
of polyethylene glycol from the ointment.
Examples of Quinolones
 Nalidixic acid
 Ciprofloxacin
 Levofloxacin
 Glatifloxacin
 Norfloxacin
 Sparfloxacin
 Fluroquinolone
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