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Transcript of Macrolide Antibiotics - Antibiotics 010.pdf  The lactone ring usually has 12, 14, or...

  • Macrolide Antibiotics

    Dr. Amged 1

  • Introduction

     The term Macrolide was originally given to antibiotics produced by species of Strptomyces.

     In 1950 the first drug of this class was isolated:Picromycin

     In 1952 Erythromycin and Carbomycin were introduced into clinic.

    Dr. Amged 2

  • General Structure

    They all contain three characteristics parts in the molecule:

    A highly substituted macrocyclic lactone: aglycone part.

    A ketone group.

    An amino desoxysugar: glycon, and in some of the macrolides, a

    neutral desoxysugar which are glycosidically attached to the

    aglycone ring.

    Dr. Amged 3

  •  The lactone ring usually has 12, 14, or 16 atoms.

     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.

    Dr. Amged 4

  • 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.

    Dr. Amged 5

  • 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. Dr. Amged 6

  • Mechanism of …continued

    Some investigations suppose that macrolides attach

    to the 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..

    Dr. Amged 7

    ../../Macrolides Mechanisms of Action and Resistance - YouTube [].flv

  • Chemical Instability of Macrolide


    • Macrolides are unstable under acidic conditions

    and undergo an intramolecular reaction to form

    an inactive cyclic ketal.

    Dr. Amged 8

  • Intramolecular ketal formation in


    Dr. Amged 9

  • Chemical Instability..

    • The cyclic ketal cause 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

    • One way of preventing acid sensitivity is to protect the hydroxy

    groups. For example, clarithromycin is a methoxy analogue of

    erythromycin which is more stable to gastric juices and has

    improved oral absorption.

    • Another method of increasing acid stability is to increase the

    size of the macrocycle to a 16-membered ring.

    Dr. Amged 11

  • Therapeutic Agents

  • Erythromycin

    It has been the subject of chemical

    manipulations to:

    a) Increase the water solubility of the drug for

    parenteral dosage forms.

    b) 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.

    Dr. Amged 13

  • Erythromycin The chemical manipulations are:

    1. Preparation of acidic salts such as glucoheptonate,

    lactobionate and stearate on the dimethyl amino group.

    2. Ester formation on the 2`-OH of the amino sugar.

    Ethylsuccinate and propionate are examples.

    Dr. Amged 14

  • Erythromycin Esters 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.

    Dr. Amged 15

  • 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


    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


    Dr. Amged 16

  • Clinical Application of 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.


    It is a good choice for penicillin-sensitive cases.

    Dr. Amged 17

  • Clarithromycin

     6-Methyl ether of erythromycin.

     Cannot undergo cyclic ketal formation, so doesn’t cause

    cramp in GI.

     Higher blood concentrations.

    More lipophilic.

     Lower doses with less intervals

    Dr. Amged 18

  • Azithromycin  Azalide, a semisynthetic macrolide with a15 membered


     Stable under acidic conditions, because it doesn’t form cyclic ketal?????

     In the treatment of urogenital infections caused by N. gonorrhoeae and Chlamidia trachomatis.

     Longer half-life.

    Dr. Amged 19

  • Dr. Amged 20

  • Dirithromycin

     A more lipophyl prodrug with high oral absorption.

     Unstable 9N,11O oxazine ring which easily hydrolysis to


     Dirithromycin is protected against gastric acid with the enteric coated


    Dr. Amged 21

  • Ketolides  Ketolides is a group of recently analogues of macrolides, developed

    to reduce side effects of macrolides and broaden their antimicrobial


     The cladinose sugar in erythromycin has been replaced with a keto-


     They are active against erythromycin resistant microorganisms.

    Dr. Amged 22

  • Telithromycin

     Telithromycin is orally effective in the treatment of community

    acquired pneumonia, acute bacterial exacerbations of chronic

    bronchitis, and acute sinusitis

    Main structure modifications are:

     The cladinose sugar in erythromycin has been replaced with a keto-

    group, and a carbamate ring has been fused to the macrocyclic ring.

     The two hydroxyl groups that cause the intramolecular ketal formation in

    erythromycin have been masked, one as a methoxy group, and the other

    as part of the carbamate ring. Dr. Amged 23

  • Dr. Amged 24

  • Miscellaneous

  • Fusidic Acid (Fucidin)

    Fusidic acid is the only steroidal antibiotic, and is isolated

    from the fermentation broth of Fusidium coccineum.

    How does it work?

    It kills bacteria by interfering with the synthesis

    of proteins inside the bacterial cells.

    Medicinal uses

     Bacterial conjunctivitis and Bacterial infections

    of the eye.

     Osteomyelitis (bone and joint infections)

     Skin and soft tissue infections

    Dr. Amged 26

  •  Clindamycin is the 7-chloro-7-deoxy

    derivative of lincomycin with greater

    antibacterial activity and better

    pharmacokinetic properties

    The Lincosamides

    Sulphur-containing antibiotics “Lincomycin and Clindamycin”

    Have similar antibacterial properties to the macrolides and

    act in the same fashion.

    Dr. Amged 27

  • Polypeptides

  • Polypeptides • These are among the most powerful bactericidal

    antibiotics but, unfortunately, their clinical use is

    limited due to undesirable side reactions,

    particularly, renal toxicity.

    • They are neutral, acidic or basic in nature.

    • Some of them are active against gram-positive

    bacteria while others as