Macrolide Antibiotics

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Macrolide Antibiotics
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Introduction

• The term Macrolide was originally given to
  antibiotics produced by species of Strptomyces.
• In 1950 the first drug of this class was
  isolatedPicromycin
• In 1952 Erythromycin and Carbomycin were
  introduced into clinic.

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General Structure

• They all contain three characteristics parts in
  the molecule
• A highly substituted macrocyclic lactone
  aglycone.
• A ketone group.
• An amino desoxysugar glycon, and in some of the
  macrolides, a neutral desoxysugar which are
  glycosisically attached to the aglycone ring.

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• The lactone ring usually has 12, 14, or 16 atoms
  and is often unsaturated having olefinic bonds
  conjugated with the ketone group.
• Having a dimethyl amino group on the glycon part,
  macrolide antibiotics are weak bases and
  different salts with pKa range of 6.0-9.0 can be
  formed on the amino group.
• Macrolides are water-insoluble molecules. Salts
  prepared by glucoheptonic and lactobionic salts
  are water soluble, whereas stearic acid and
  laurylsulfuric acid salts are water-insoluble.
• Macrolides are stable in aqueous solutions at or
  below room temperature. They are unstable in
  acidic or basic conditions or at high
  temperatures.

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The First Macrolide Whose Structure was Fully
Elucidated

• Has the smallest aglycone, with a 12 membered
  ring.
• It has only the amino sugar in its molecule
  (desosamine).

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Mechanism of Antimicrobial Activity

• Macrolides attach to the 50s portion of bacterial
  ribosomes and inhibit the protein synthesis.
• They block the enzymes that catalyse the transfer
  of the new amino acid residue to the peptide
  chain, that is, prevent elongation in prokaryotic
  cells.

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Mechanism of Microbial Resistance

• Methylation of a guanine residue on ribosomal RNA
  leads to lower affinity toward macrolides. The
  mutant rRNA has a lower ability for protein
  synthesis too. The macrolide producing
  microorganism uses the same way to protect its
  rRNAs against this antibiotic.
• Hypothesis Maybe the antibiotic producing
  microorganisms are the source of R factors that
  cause the microbial reistance .
• In some bacterial strains, an active efflux
  system is responsible for the resistance against
  macrolides.

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Mechanism of continued

• Some investigations suppose that macrolides
  attach to the 23 rRNA through an interaction with
  the Adenine 2058 in the region V of it. Mutation
  of this nucleotide causes a 10000 fold decrease
  in the attachment of the drug and a resistance in
  the bacteria against macrolides.
• Lack of cell wall permeability to macrolides is
  the reason why G(-) bacteria are resistant to
  antibacterial effects of these agents..

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Spectrum of Antibacterial Activity

• Macrolides are similar to penicillins regarding
  their spectrum of activity.
• They are effective against penicillin-resistant
  strains.
• Macrolides are effective against most of the G()
  bacteria, cocci or bacillus, they have antibiotic
  activity against G(-) cocci ,especially Neisseria
  Spp too.
• Macrolide antibiotics are effective against
  Mycoplasma, Clamidia, Campylobacter and
  Legionella in contrast to penicillins.
• They are less effective against G(-) bacteria,
  though some strains of H. influenza and Brucella
  are sensitive to the antibacterial activity of
  this class of antibiotics.

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Chemical Instability of Macrolide Antibiotics

• Macrolides are unstable under acidic conditions
  and undergo an intramolecular reaction to form an
  inactive cyclic ketal.

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Chemical Instability..

• The cyclic ketal is is the cause of intestinal
  cramp which is reported after the use of
  erythromycin.
• Water-insoluble salts and enteric coated dosage
  forms of macrolides have less such a side effect.
• Water insoluble forms cannot take part in the
  reactions which occur in aqueous solutions.
• Stearate salt is an example of insoluble salts
  of erytromycin.

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Therapeutic AgentsErythromycin

• It is isolated from Streptomyces erythraeus in
  1952.
• The aglycon, amino sugar, and the neutral sugar
  are named erythronolide, desosamine, and
  cladinose respectively.

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• It has been the subject of chemical manipulations
  to
• Increase the water solubility of the drug for
  parenteral dosage forms.
• Increase the lipid solubility and hence chemical
  stability of the drug against aqueous acidic
  conditions as well as increase in oral absorption
  and masking the bitter taste of the drug.
• The chemical manipulations are
• Preparation of acidic salts such as
  glucoheptonate, lactobionate and stearate on the
  dimethyl amino group.
• Ester formation on the 2-OH of the amino sugar.
  Ethylsuccinate and propionate are examples.

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Erythromycin Esters

• Erythromycin Estolate
• 2 propionyl ester and N-lauryl sulfate salt of
  erythromycin.
• A lipid-soluble, acid-stable prodrug which
  undergoes hydrolysis in blood or tissue after
  absorption.
• The antibacterial form is the pure erythromycin.
• Erythromycin Ethyl Succinate
• A mixed double ester prodrug of erythromycin.
• Better oral absorption.
• In oral suspensions for children, without the
  bitter taste.
• Erythromycin Propionate
• A lipid-soluble ester of propionic acid.
• Better oral absorption.

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Erythromycin Salts

• Erythromycin Stearate
• A lipid-soluble salt of stearic acid.
• Better oral absorption.
• Acid-sensitive. Enteric coated form is
  Acid-stable.
• In the small intestine base exchange occurs and
  free erythromycin releases.
• Erythromycin Lactobionate
• A water-soluble salt of lactobionic acid for
  parenteral dosage forms.
• Erythromycin Glucoheptonate
• A water-soluble salt of glucoheptonic acid for
  parenteral dosage forms.

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Clinical Applicationof Erythromycin

• It is used to treat
• The upper part of the respiratory tract
  infections,
• Soft tissue G() infections,
• Mycoplasma pneumonia caused pneumonia,
  Campylobacter jejuni enteritis,
• Clamidia infections.
• Gonorrhoea.
• It is a good choice for penicillin-sensitive
  cases.

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Clarithromycin

• 6-Methyl ether of erythromycin.
• Cannot undergo cyclic ketal formation, so doesnt
  cause cramp in GI.
• Higher blood concentrations.
• More lipophyl.
• Lower doses with less intervals.

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Azithromycin

• Azalide, a semisynthetic macrolide with a15
  membered ring.
• Stable under acidic conditions, because it
  doesnt form cyclic ketal.
• In the treatment of urogenital infections caused
  by N. gonorrhoeae and Chlamidia trachomatis.
• Longer half-life.

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Dirithromycin

• A more lipophyl prodrug with high oral
  absorption.
• Unstable 9N,11O oxazine ring which easily
  hydrolysis to erythromyclamine.

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• Erythromyclamin is another semisynthetic
  derivative of erythromycin with 9-amino instead
  of 9-keto group.
• It has the same antibacterial effects as
  erythromycin.
• Less oral absorption than erythromycin has lead
  chemists to prepare more lipophyl prodrug,
  dirithromycin.
• Dirithromycin is protected against gastric acid
  with the enteric coated form.
• It is readily absorbed orally, but has low plasma
  concentration because of high volume of
  distribution.
• Infections of the upper and lower parts of
  respiratory system with only one oral dose.

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TroleandomycinOleandomycin

• Oleandomycin is isolated from Streptomyces
  antibuticus. Troleandomycin is a prodrug of the
  former.
• Bacteriostatic effects the same as erythromycin.