Aminoglycosides,Aminocyclitols,Source,Structures of streptomycin,Dihydrostreptomycin,A mention of other aminoglycoside antibiotics,Acid hydrolysis,Mechanism of action,SAR,Dihydrostreptomycin and its importance,therapeutic uses, toxicity.
2. Amino glycoside antibiotics contain an amino cyclitol moiety to
which aminosugars are linked glycosidically.
They may be more correctly called aminocyclitol antibiotics.
Aminoglycosides are a group of antibiotics effictive against gram+ve and
gram-ve organismsas well as micoplasma .
Most of the aminoglycosides antibiotics are dirived from genus streptomyces
species, important one is streptomycin.
Aminoglycoside antibiotics are also referred as aminocyclitol antibiotics,
because they consist of a highly substituted ring called aminocyclitol ring i.e.
1,3 di amino cyclohexane central ring.
(pharmacophoric 1,3-diaminoinositol moiety consisting of either
streptamine,2-deoxystreptamine
(Or) spectinamine.)
Streptidine = streptomycin
Neomycin
Gentamycin
kanamycin
Tobramycin
All aminoglycosides in this class possess one amino hexose sugar.but
some antibiotics like
Streptomycin,neomycin,paramomycin possess a pentonse sugar.
Due to several amino groups aminoglycosides are basic in nature.
Deoxy streptamine
(Aminocyclitols)
The chemistry,spectrum,potency,toxicity,
And pharmacokinetics of these agents
are a function of the specific identity
of the diaminoinositol unit and the
arrangement and identity of the
attachments.
3. Aminocyclitols???
Cyclohexanes with several substituted or
unsubstituted amino and hydroxyl groups which
bring them high water solubility.
Streptidine and Streptamine can be called 1,3-
diguanidino and 1,3-diamino inositol, respectively.
1,3 Diaminoinositol moieties in
aminoglycosides
4. General characteristics of amino glycosides
Amino glycosides are polycations and are highly
polar they are water soluble.
They are basic and form salts with acids.
They are poorly absorbed after oral administration
that’s why they do well when given parentally.
Because aminoglycosides are quickly broken down
in the stomach, these antibiotics can't be given
orally, but instead must be injected.
Aminoglycosides can cross the placental barrier.
They are unable to cross blood brain barrier so
they can’t be used for the treatment of meningitis
unless they are injected directly in to the CNS.
5. In the 1940’s soil actinomycetes bacteria were systematically
screened for the elaboration of antimicrobial substances
6. Streptomycin
isolated in 1943 from Streptomyces griseus
-
6 membered ring with 2 glycosylated aminosugars
- cationic compound
Classified as an Aminoglycoside.
8. STYPTOMYCIN(STN)
Streptomycin is the first aminoglycoside antibiotic which was
isolated from the actinomycetes bacteria Streptomyces griseus
and several related soil microorganisms.
Streptomycin was first discovered in 1943 by Selman abraham
wakesman and received a Nobel prize in 1952.
It was introduced in 1943 primarily for the treatment of
tuberculosis.
Chemistry of streptomycin:
Streptomycin is a triacidic base and has an aldose sugar.
It is a water soluble with basic properties.
The hydrophilic nature of streptomcin results in very poor absorption
from GIT.
The two guanidino groups attached to the streptidine exhibits
strong basic nature.
The amino sugars attached to streptidine by means of
glycosidic linkages.
9. The methyl amino group attach to N-methyl-L-glucosamine exhibits
weakly basic natue.
Streptomycin is made up of 3 basic structural units called ….
Streptidine(a diguanidino compound)
Streptose (a aldose sugar)
N-methyl-L-glucosamine unit.
Physico- chemical properties:
Colour: colourless.
Odour : odourless.
State : Streptomycin sulphate and
streptomycin chloride available in the form of white
powdery solid.
Solubility : Easily soluble in water insoluble in acetone.
Stability: It is stable at a temp. less than 280
c and
solutions of streptomycin are stable at pH (4.5-7).
10. Strepto
biosamine
Weakly basic
Streptomycin is made up
Of 3 basic structural units
Called…
1. Streptidine(adiguanidino
compound)
2. Streptose (a addose sugar)
3. N-methyl-L-glucosamine.
11. SAR of streptomycin
Modification of α-streptose portion of streptomycin has been
extensively studied.
1. Reduction of aldehyde to alcohol results in a compound
dihyrostreptomycin activity is similar to streptomycin but producing
severe deafness.
2. Oxidation of aldehyde group to a
(oxime,semicarbazone,phenylhydrazone) Schiff base
derivatives results in inactive analogues.
3. Oxidation of –CH3 group in α-streptose to a methylene hydroxy
gives an active analogous but has no advantage over STM.
4. Modification of amino methyl group in the glucosamine by
demethylation and replace by larger alkyl groups reduces activity.
5. In N-methyl-L-glucosamine( –NHCH3 group) is very essential for the
acivity.
6. Guanidino groups streptidine ring are essential .Replacement of
guanidino groups reduces the antibacterial activity.
7. In N-methyl –L-glucosamine the “N” atom should be secondary
amine.
12. DIHYDROSTREPTOMYCIN
The only difference in the structure of streptomycin and dihydrostreptomycin is the
Presence of a hydroxyl alcoholic group(-CH20H) in place of –CHO group of
Streptose moiety. the –CHO group of streptomycin is replaced by –CH2OH group)
It is a semisynthetic derivative obtained by the catalytic hydrogenation of
Streptomycin.
It is formed by the hydrogenation of aldehydic carbonyl group of the streptose moiety
Present in streptomycin to a primary alcohol.
Infact it is more stable than streptomycin.
It has similar mechanism of action, pharmacokinetic aspects and toxicological properties
as that of streptomycin.
It has generally fewer side effects than streptomycin but it has a higher risk of
Ototoxicity than streptomycin.
Spectrum of activity:
It shows broad spectrum of activity in the treatment of systemic infections caused by
Gram-ve mo’s Brucella,Haemophilus,shigella,Klebsiella,pasteurella and most effective
Against Mycobacterium tuberculi.
Toxic effects/adverse effects:
Ototocicity,Nephrotoxicity,Neuromuscular paralysis and allergic reactions.
IMPORTANCE OF DIHYDROSTREPTOMYCIN:
Treatment of tuberculosis in various animals.
It is less neurotoxic than streptomycin but high frequency of ototoxicity in humans.
Dihydrostreptomycin is used in combination with procaine penicillin to treat systemic infections
It is not recommended for humans as it is ototoxic and hence mostly used for veterinary
purposes for the treatment of systemic infections.
The therapeutic dose in animals is 11mg/kg body weight given through IM route.
13. Penicillin G procaine ------ 200,000/IU
Dihydrostreptomycin sulphate-------- 200,000/IU
The combination of penicillin G procaine and
dihydrostreptomycin acts additive and in some
cases synergistic.
Procaine penicillin G is a small-spectrum penicillin
with a bactericidal action against mainly Gram-
positive bacteria like Campylobacter, Clostridium,
Corynebacterium, Erysipelothrix, Haemophilus,
Listeria, penicillinase negative Staphylococcus and
Streptococcus spp.
INDICATIONS
Arthritis, mastitis and gastrointestinal, respiratory
and urinary tract infection caused by penicillin and
dihydrostreptomycin sensitive micro-organisms,
like Campylobacter, Clostridium, Corynebacterium,
E.coli, Erysipelothrix, Haemophllus, Klebsiolla,
Listeria, Pasteurella, Salmonella, and
Staphylococcus spp., in calves, cattle, goats, sheep
and swine.
Infections due to susceptible organisms,
respiratory, reproductive and urinary tract
infections, pre- and post- operative
prophylaxis, mycotic dermatitis, abscess,inflammation and
allergic conditions in cattle,horses,cows,gots,pigs,sheeps.
Dihydrostreptomycin
Alone used mainly
against
E.coli,
Klebsiella,
Pasteurella,
Salmonella,
Strephylococcus.
14. Dihydro streptomycin +penicillin combination is currently used
as broad-spectrum antibiotics for the treatment of infections due
to a wide range of Gram-positive and Gram-negative bacteria.
These include foot abscess.
osteomyelitis, peritonitis, septicaemia, scours, pneumonia,
cystitis, peracute mastitis.
post-operative prophylaxis, metritis, bacterial enteritis,
leptospirosis.
actinomycosis/actinobacillosis and respiratory, reproductive
and urinary tract infections.
They are also widely used in footrot eradication and control
programs.
dihydro) streptomycin only products for use in cattle, sheep,pigs or
poultry.
prophylactic leptospirosis treatment of cattle for live export
(Leptospirosis is a zoonotic disease with serious human health
implications )
15. Dihydrostreptomycin:
OHC
It is an antibiotic consisting
of hydrogenated form of
Streptomycin.
Aldehyde (-CHO)group
of streptose moiety
is replaced by
-CH2OH group.
17. Mechanism of Action
1. Ionic binding to outer membrane lipopolysaccharides & proteins
2. Disruption of cell membrane permeability
- Displace Ca and Mg
- Transient hole formation in the cell membrane
- Uptake of the aminoglycoside through the holes
3. Binding to 30 S ribosomal subunit
- Interfere with translational accuracy leading to miscoding
- Decrease in protein synthesis
18. Mechanism of Action of Aminoglycosides
Inhibition of protein biosynthesis initiation
upon attachment to 30s portion of
ribosomes.
Misreading mutation of the genetic code
and the synthesis of nonesense proteins
which are not normal proteins so they
cannot take part in cellular activities.
Nonesense proteins disturb the
semipermeability of the bacterial cell and
aminoglycoside molecules enter the cell
easily and kill it.
19. Mechanisms of action
Aminoglycosides have several potential antibiotic mechanisms, some as
protein synthesis inhibitors, although their exact mechanism of action is
not fully known:
They interfere with the proofreading process, causing increased rate
of error in synthesis with premature termination.
Also, there is evidence of inhibition of ribosomal translocation where
the peptidyl-tRNA moves from the A-site to the P-site
They can also disrupt the integrity of bacterial cell membrane.
Depending on their concentration they act as bactereostatic or
bactericidal agents.
The protein synthesis inhibition of aminoglycosides does not usually produce
a bactericidal effect.
Recent experimental studies show that the initial site of action is the
outer bacterial membrane.
The cationic antibiotic molecules create fissures in the outer cell
membrane, resulting in leakage of intracellular contents and
enhanced antibiotic uptake. This rapid action at the outer membrane
probably accounts for most of the bactericidal activity.
Aminoglycosides competitively displace cell biofilm-associated Mg2+ and
Ca2+ that link the polysaccharides of adjacent lipopolysaccharide molecules.
"The result is shedding of cell membrane blebs, with formation of transient
holes in the cell wall and disruption of the normal permeability of the
cell wall. This action alone may be sufficient to kill most susceptible Gram-
negative bacteria before the aminoglycoside has a chance to reach the 30S
ribosome
21. Freeze initiation
Block peptide
bond formation
Misreading of mRNA
p-Site
(Peptidyl site)
on which the
t-RNA holds the
Elongated peptide chain.
(A-site)
Amino acetyl
t-RNA binding
site.(attachment of
Incomming amino
Acid by t-RNA.
(Aminoglycosides
blocks translocationhere)
Chloramphenical
Blocks transpeptidation
22. Therapeutic uses of aminoglcosides:
The most frequent use of aminoglycosides is empiric therapy for serious infections such as
septicaemia.
complicated intraabdominal infections
complicated urinary tract infections,
respiratory tract infections.
Energy is needed for aminoglycoside uptake into the bacterial cell
Anaerobes have less energy available for this uptake, so aminoglycosides are less active
against anaerobes
. Aminoglycosides are useful primarily in infections involving bacteria,
such aerobic gram –ve Pseudomonas
Actinobacter
and Enterobacter
In addition, some Mycobacteria, including the bacteria that cause tuberculosis, are
susceptible to aminoglycosides.
Streptomycin was the first effective drug in the treatment of tuberculosis
In the past the aminoglycosides have been used in conjunction with beta-lactam
antibiotics in streptococcal infections for their synergistic effects, particularly in
enocarditis.
One of the most frequent combinations is ampicillin (a beta-lactam, or penicillin-related
antibiotic) and gentamicin.
Often, hospital staff refer to this combination as "amp and gent" or more recently called
"pen and gent" for penicillin and gentamicin.
Experimentation with aminoglycosides as a treatment of cystic fibrosis (CF).
Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi, and viruses.
frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment
makes physicians reluctant to use these compounds in everyday practice
although more research still needs to be done in order to overcome this problem entirely.
24. Toxicity/Adverse effects
All aminoglycosides are ototoxic and nephrotoxic.
Ototoxicity and nephrotoxicity are more likely to be encountered when
therapy is continued for more than 5 days, at higher doses, in the elderly,
and in the setting of renal insufficiency.
Concurrent use with loop diuretics (eg, furosemide, ethacrynic
acid) or other nephrotoxic antimicrobial agents (vancomycin,
amphotericin) can potentiate nephro-toxicity and should be avoided.
Ototoxicity can manifest as auditory damage, resulting
in tinnitus and high-frequency hearing loss initially,
or as vestibular damage, evident by vertigo, ataxia,
and loss of balance.
25. Streptomycin and gentamicin are the most vestibulotoxic.
Nephrotoxicity results in rising serum creatinine levels or reduced
creatinine clearance.
Neomycin, kanamycin, and amikacin are the most
ototoxic agents.
Neomycin, tobramycin, and gentamicin are the most nephrotoxic.
In very high doses, aminoglycosides can produce a curare-like effect
with neuromuscular blockade that results in respiratory paralysis. This
paralysis is usually reversible by calcium gluconate
(given promptly) or neostigmine.
Hypersensitivity occurs infrequently.
26. OTOTOXICITY:
Progressively damage the sensory cells of the cochlea and vestibular apparatus
Killed sensory cells do not regenerate
Loss of hearing, vertigo, ataxia, and loss of balance
Vistibular toxicity:
Nausea, vomiting, cold sweats
Vertigo
Aaxia
Nystagmus.
Cochlear damage:
Varying degrees of hearing loss
High frequency tones
Tinnitus
Sense of fullness or aching in the ears.
27. Vestibular damage
gentamycin and streptomycin
Cochlear damage
kanamycin, amikacin, and neomycin
Streptomycin deafness
Equally affect
Tobramycin.
How to avoid ototoxicity:
Renal, auditory, and vestibular function
- assessed before, during, and following therapy
Aminoglycoside serum concentrations
Avoiding prolonged therapy and ototoxic agents
Maintain hydration, urine output, and normal serum electrolytes
Recommend : stop the aminoglycoside at the first sign of
29. Nephrotoxicity:
Pathophysiology
More polycationic like gentamicin and neomycin, enter proximal tubular cells by
pinocytosis.
Inhibit lysosomal enzymes, the vesicles accumulate ( cytosegresomes )
Excessive numbers of these apparently kill the cells, producing severe
toxicity.
Proximal tubular necrosis, may not see clinically
Acute nonoliguric renal failure
Proximal tubular damage causes the whole nephron to fail increased serum aminoglycoside concentrations.
Proximal renal tubular cells regenerate
Nephrotoxicity is not limited to proximal tubular toxicity but also may involve the medullar region (Henle loop and
collecting duct) of the nephron.
30. Risk factors:
Advanced age
Sepsis, Shock
Prolonged aminoglycoside usage
Underlying renal insufficiency
Coadministration of other nephrotoxic agents
Dehydration
Decreased albumin or poor nutritional status
Pneumonia
Hypercalcemia
Leukemia
Rapidly fatal illness
Liver or kidney disease
Pleural effusion, ascites
Reduced aminoglycoside clearance
Elevated initial steady-state concentration
31. Which one is the most dangerous?
• Based on dose-response data
• Gentamicin > Tobramycin & amikacin > Netilmicin
•
Number of free amino groups & relative nephrotoxicity.
How to treat?
Supportive
Discontinuation
Dialysis
How to minimize nephrotoxicity?
Renal function tests
Serum creatinine levels
Abnormal urinary sediment
Leukocyturia
Elevated levels of beta-2 microglobulins excreted in the urine
Once-daily Dose
32. Neuromuscular paralysis
Inhibit Ca++
into nerve on depolarization
required for exocytotic ACh release
Ca++
injections can improve release
Weakness at doses on top end of range if any renal problem
Respiratory paralysis if use for lavage of peritoneal or pleural cavity.
To prevent all these side effects:
Not Using Aminiglycoside !!
There are antibiotics with equal or better sensitivity profiles
than aminoglycosides against GNRs and Pseudomonas.
Once Daily Dose !!
Nephrotoxicity
Monitoring !!
33. CHLORAMPHENICOL (chloromycetin)
Chloramphenicol was originally derived from the bacterium Streptomyces
venezuelae, isolated by David Gottlieb, and introduced into clinical
practice in 1949, under the trade name Chloromycetin.
It was the first antibiotic to be manufactured synthetically on a large
scale.
Chloramphenicol is a broad-spectrum antibiotic that acts as a
bacteriostatic, but at higher concentrations can act as a bactericidal.
A broad spectrum antibiotic which is a nitrobenzine derivative
derived from dichloro aceticacid.
Structure and chemical characteristics
Chloramphenicol contains a nitrobenzene ring, an amide bond, and an
alcohol function.
The presence of chlorides in biologically produced organic molecules is
unusual. The nitrobenzene is relevant because it leads to the formation of
aromatic amines which may be carcinogenic.
The amide is hydrolyzed by some resistant bacteria leading inactivation.
The alcohol serves as a functional group facilitating the formation of
esters that improve chloramphenicol's water solubility. Chloramphenicol
base has low water solubility and high lipid (in organic alcohols)
solubility. Its palmitate ester is similar, but the succinate ester has high
water solubility.
34. 1. moecular formula is C11H12Cl2N2O5
2.Basic nucleus is P-nitrobenzene contains a
side chain at p-position to –No2 group.
3.Side chain contains one –OH group at “b”
and one hydroxymethyl group at “a”.
4. on the “a” carbon presence of 2,2-dichloro-
acetamide moiety hence the side chain can
also be named as acyl amido propanediol.
5. Stereochemistry of chloramphenicol exists
in 2 pairs of enanteomers(optically active
compounds which are mirror images.
6. I contains 2 chiral carbons .
7. 4 enantiomers are possibe.
one is D and L threo– (2 identical groups
are opposite sides of chiral carbons)
Erythro ( 2 identical groups are on same
side of chiral carbon atom.
out of 4 enatiomers D- Threo form shows
biological activity..
* a
*
b
36. Mechanism of action:
Chloramphenicol is bacteriostatic (that is, it stops bacterial growth).
It is a protein synthesis inhibitor
Chloramphenicol binds to the 50S subunit of ribosomes and appears to
act by inhibiting the movement of ribosomes along mRNA,probably
inhibiting the peptidyl transferase reaction by which the peptide chain is
extend.
-----------------------------------------------------------------------------------
Since it binds to the same region as macrolides,lincosamides these drugs
can’t be used in combination.
The nitrogroup and both alcohol groups is also important but can be
replaced by other electronegative groups.
Bacteria with resistance to the drug contain an enzyme called
Chloramphenicol acetyltransferase, which catalyses the acylation of
the hydroxyl groups.
40. Side effects of chloramphenicol
Abdominal pain; Bloating; Blood disorders which may be serious;
Diarrhoea; Fatigue; Fever; Headache; Nausea and vomiting;
Newborn babies with immature liver function can get a serious side effect
where the skin develops a grey colour and there is circulatory collapse
(grey syndrome)
Pins and needles (paraesthesia);
Rash
Sore throat
Stomach upset
Tingling of the hands or feet
Unusual bleeding or bruising
Vision changes or eye pain
Visual disturbances
Vomiting;
This drug is quite toxic to bone marrow (supression of bonemarrow).The
nitro group is suspecdted to be responsible for this, although intestinal
bacteria are capable of reducing this group to an amino group.
aplastic anaemia
Anorexia
41. Uses of chloramphenicol Chloramphenicol is an antibiotic used to treat a variety of bacterial
infections
In some regions in the world chloramphenicol is the drug of the choice
for the treatment of typhoid when more expensive drugs cannot
be afforded.
It is also widely used against eye and ear infections.
Meningitis,Anthrax,Brucellosis
Burkholderia Infections (in cystic fibrosis patients, immunocompromised patients )
Chlamydial Infections
Clostridium Infections
Vibrio (InfectionsTreatment of cholera caused by Vibrio cholerae)
Ehrlichiosis,Plague,Rat-bite Fever
Rickettsial Infections, Haemophilus influenzae infection
Chloramphenicol treats only bacterial eye infections. Chloramphenicol
will not work for other types of eye infections
anti-infective ear preparations.
Those bacteria sensitive to this drug include clostridium, chlamydia,, salmonella.
Chloramphenicol has also shown activity against Mycoplasma.
42. Drug Interactions or Contraindications
Chloramphenicol is contraindicated if another drug can be used
instead due to its potential to cause bone marrow depression.
Not recommended for use with Tylan, azithromycin or
erythromycin, as they may be antagonistic with chloramphenicol.
Acetaminophen will elevate chloramphenicol levels.
Chloramphenicol has the potential to antagonize bactericidal
activity of the penicillins and aminoglycosides.
Rifampin may decrease serum chloramphenicol levels.
Chloramphenicol is also not recommended to be given in pregnant or lactating
animals due to its ability to cross the placenta and passed in breast milk.
Adverse Reactions
Avoid using if impaired hepatic or kidney function is present. Prolonged use may
result in suprainfections.
ENT: optic neuritis
GI: diarrhea, disturbance of intestinal flora
Hematologic: irreversible idiosyncratic aplastic anemia (identified in humans),
dose-related bone marrow suppression with long term therapy (reversible once
drug stopped)
Hepatic: jaundice
Other: anaphylaxis
May falsely elevate urine glucose levels
43. Spectrum of Antimicrobial Activity
Aminoglycosides are broad-spectrum antibiotics effective in:
1. Systemic Infections caused by aerobic G(-) bacillus
(klebsiella, proteus, enterobacters).
2. Tuberculosis, Brucellusis, Tularaemia and yersinia infections.
3. Amoebic dysentery, shigellosis and salmonellosis.
4. Pneumonia and urinary infections caused by Pseudomona
aeroginosa.
G(+) and G(-) aerobic cocci except staphylococci and
anaerobic bacteria are less susceptible.
44. Microbial Resistance against
Aminoglycosides
Resistant strains have emerged against
streptomycin, kanamycin and gentamycin
in clinic.
R factor is resposible for the production of
aminoglycoside deactivating enzymes:
1) Acetyl transferases (AAC)
2) Phosphotransferases (APH),
3) Nucleotidyl transferases (ANT)
These enzymes transfer to hydroxyl and
amino groups of the drug.
45. Aminoglycoside Deactivating Enzymes
AAC acetylates 3-NH2 of the ring II, and 2`, 6`- NH2 of the
ring I.
APH phosphorylates 3`-OHof the ring I and 2``-OH of the
ring III.
ANT adenylates 2``,4``-OH of the ring III and 4`-OH of
the ring I.
O
O
O
O
OH
NH2
OH
H2N
OH
NH2
H2N
HO
H2N
HO
OH
1 2
3
45
6
1'
2'
4'
1''
3'
2''
5'
3''
5''
4''
6''
6'
I
II
III
ANT-4'
ANT-4''
ANT-2''
, APH-2''
AAC- 6'
AAC- 2'
APH- 3'
AAC- 3
Kanamycin B
47. Gentamicin
Isolated from cultures of Micromonospora purpurea.
The suffix “micin” denotes its origin.
It is used against urinary infections caused by G(-) and
pseudomona.
O
O
O
O
HC
NH2
H2N
OH
NH
H3C
NH2
HO
1''
2''3''4''
5''
1'
2'
3'
4'
6'
5'
1
23
4
5 6
Garosamine
2-Deoxystreptamine
Gentamicin C1: R1=R2 = CH3
Gentamicin C2: R1 = CH3 ; R2 = H
Gentamicin C1a: R1=R2 = H
OH
CH3
NHR2R1
Lacks 3`-OH
APH Resistant
Axial and tertiary 4``-OH instead of
equatorial secondary 4``-OH in Kanamycin
ANT Resistant
Secondary amino group at 6`-NH2 in
Gentamycin C1, spacial hynderance
AAC Resisistant
I
II
III
48. Tobramycin
Isolated from cultures of Streptomyces
tenebrarius.
Antimicrobial activity against resistance
P.aeroginosa.
O
O
O
O
H2C
NH2
H2N
OH
NH2
HO
NH2
HO
2-Deoxystreptamine
Tobramycin
HOH2C
HO
1
1''
2''3''4''
5''
1'
5'
4'
3' 2'
3
4
5 6
2
6''
Lacks 3`-OH
APH Resistant
51. Tobramycin
Isolated from cultures of Streptomyces
tenebrarius.
Antimicrobial activity against resistance
P.aeroginosa.
O
O
O
O
H2C
NH2
H2N
OH
NH2
HO
NH2
HO
2-Deoxystreptamine
Tobramycin
HOH2C
HO
1
1''
2''3''4''
5''
1'
5'
4'
3' 2'
3
4
5 6
2
6''
Lacks 3`-OH
APH Resistant
53. Spectinomycin
An unusual aminoglycoside isolated from cultures
of streptomyces spectabilis.
The sugar portion has a carbonyl group and is
fused through glycosidic bonds to the aminocyclitol
portion, spectinamine.
It is used in a single dose against Neisseria
gonhorea.
O
O
O
CH3
O
H3CHN
OH
NHCH3 OH
HO
Spectinomycin
Sugar
Spectinamine
55. Mechanism of Chemical incompatility of
Aminoglycosides with β-lactams
Acylation of
aminocyclitol
portion by the β-
lactam molecule.
Begins with
nucleophilic
addition of the
amino group to the
carbonyl group of
β-lactam ring.
N
O
NHCOR
HOOC
O
NHCOR
HN
HO
O
O
SUGAR
NH2
N
SUGAR
HOOC
H2N
HO
O
O
SUGAR
NH2
SUGAR