Macrolides are a class of broad-spectrum antibiotics produced by Streptomyces, characterized by a macrolide ring structure, and function primarily by inhibiting protein synthesis on the 50s ribosomal subunit. Significant examples include erythromycin, azithromycin, and clarithromycin, with azithromycin noted for its superior pharmacokinetics and reduced side effects. Recent research indicates that newer macrolides like azithromycin may provide enhanced antimicrobial activity and lower frequency of administration compared to older drugs.

1. Macrolides
Macrolides Antibiotics
• The macrolides are a group of antibiotics produced by various strains of
Streptomyces and having a macrolide ring
structure linked to one or more sugars.
• They act by inhibiting protein synthesis, specifically by blocking the 50S
ribosomal subunit.
• They are broad spectrum antibiotics.
• Macrolides typically display bacteriostatic activity, but may be
bactericidal when present at high concentration
against very susceptible organisms
Examples: Erythromycin, Azithromycin,
Clarithromycin, Roxithromycin etc.

2. • Among the many antibiotics isolated from the actinomycetes is the group of chemically related compounds
called the macrolides.
• In 1950, picromycin, the first of this group to be identified as a macrolide compound, was first reported in
1952, erythromycin and carbomycin were reported as new antibiotics and they were followed in
subsequent years by other macrolides.
• Currently, more than 40 such compounds are known, and new ones are likely to appear in the future. 0f all
of these, only two erythromycin and oleandomycin have been available consistently for medical use in the
United States.
• In recent years, interest has shifted away from novel macrolides isolated from soil samples (e.g..
Spiramycin, josamycin, and rosamicin), all of which thus far have proved to be clinically inferior to
crythromycin and semisynthetic derivatives of erythromycin.
• Azithromycin, which have superior pharmacokinetic properties due to their enhanced acid stability and
improved distribution properties.

4. General Structure of Macrolide Antibiotics

5. STRUCTURE ACTIVITY RELATIONSHIP
3
4
6
5
7
8
9
10
11
12
13
14
1
2

6. At C2: As macrolide are unstable in acidic pH, a number of stratergies have been
utilized to improve the acidic stability of erythromycin – fluorination of
erythromycin
At C9, the addition of hydroxylamine to the ketone to form oxime eg
roxythromycin.
At C6, Alteration of C6 hydroxyl group: nucleophilic functionality which initiates
erythromycin degradation. The azalides (azithromycin) are semi synthetic 15
membered congeners in which a nitrogen atom has been introduced to expand
a 14 membered precursor leads to an extended spectrum of action

7. Mechanism Of Action Of Macrolide Antibiotics
Macrolides binds with 50s ribosomal
subunit
Inhibits peptide transferase activity
Interferes with translocation of amino
acids during translocation & assembly
of proteins
Inhibits protein synthesis

8. ERYTHROMYCINE
Source: Isolated from Streptomyces
erythreus
Dosage forms:
➢Oral and topical dosage forms.
➢Enteric coted and delayed release
dosage forms.
Drug interactions:
➢Anticoagulants
➢Benzodiazepines
➢Antihistaminic drugs
Physical properties:
➢Yellow to white crystalline powder.
➢Soluble in alcohol, slightly soluble in
water.
➢Stable at neutral pH.

9. Erythromycin
• Chemistry structure
molecular formula :-C37 H67 NO13
Molecular weight :- 733.93 g/mol

10. Structure activity relationship
Macrolide ring
❑erythromycin core structure is a 14 membered lactone ring called
erythronolide .
❑this macrocyclic structure is essential for binding to the bacterial ribosome.
❑Size :- 14- membered ring for optimal activity
❑Substitutions :- alkyl, hydroxyl, or amino groups at C-4,C-6, OR C-8 positions
can enhance activity

11. Sugar moieties
•
Erythromycin has two sugar molecules
attached to the lactone ring
L cladinose : at position 3
essential for the activity against
gram positive bacteria this sugar enhance
the binding affinity to the ribosome
Desosamine : at position 5
important for activity against gram-
negative bacteria
Other sugar ( e.g mycarose , forosamine )
these are also responsible for enchancing
the stability and activity.

12. • Functional group
• The presence of hydroxyl group (-OH) and keto group (=O) on the
lactone ring are critical for the antibiotic activity.
• Position ;- hydroxyl group at C-2’ , C-4’ and C-6’ positions essential
• These group interact with the 23S ribosomal RNA in the 50S subunit
of bacteria inhibit protein synthesis.
• Presence :- it enhance the activity against gram-positive bacteria
• Ester group
Formation :- lactonization essential for macrolide ring formation
Substitution :- alkyl or aryl esters can enhance activity

13. SAR tendency
• Increased lipophilicity :- enchances activity
against gram negative bacteria
• Increased hydrophilicity :- enhance activity
against gram positive bacteria
• Steric hindrance :- can reduce activity

14. Azithromycin

15. Chemistry of azithromycin
• Chemical formula :- C38H72N2O12
• Azithromycin is a derivative of erythromycin
and features a 15 membered lactone ring
• Which is one of it’s key structural element.
• it also has :
• A desosamine sugar at position 5 , which
effect in ribosomal binding.
• A cladinose sugar at position 3 , enhancing
itt’s biological activity

16. Structure activity relationship

17. Properties:
1.Nitrogen containing 15-membered lacton ring macrolides(azalides).
2. Stable under acidic conditions, because it does not form cyclic
ketal. 3.Strongest activity against mycoplasma pneumoniae.
4.More effective on gram-negative bacteria.
5. Well tolerated
Uses:
➢ In the treatment of Urogenital infections caused by N.gonorrhoeae and
Chlamydia trachomatis.
➢ For the treatment of respiratory tract infections.
➢ Pregnant women infected with scrub typhus: Azithromycin can suitable
for doxycyclin

18. Clarithromycin

19. Advantages
➢ Cannot undergo cyclic ketal formation, so doesn't cause cramp
in GI
➢ More lipophyl.
➢ Lower doses with less intervals.
Uses:
➢ Atypical mycobacterial infection
➢ Resistant leprosy
➢ Toxoplasmosis
➢ H.Pylori induced peptic ulcers

20. ROXITHROMYCINE

21. Properties:
Semi-synthetic 14-membered ring macrolide antibiotic in which the erythronolide
lactone ring has been altered to prevent inactivation in the milieu.
Uses:
➢ Active against both gram (+) & gram (-).
➢ Treatment of skin, dental & genital infections.
➢ Treatment of upper & lower respiratory tract infections.

22. Analogues of macrolide natural products
• Macrolide natural products with 12, 14, or 16 membered rings and their
semisynthetic derivatives are important clinically relevant compounds
predominantly used for the treatment of various types of cancer.
• Macrolactams are easily synthesized and offer access to multiple analogues
with chemical and enzymatic stability as well as desirable biological properties.
15-Aza-epothilone B
[Ixabepilone]

23. 15-Aza-salicylihalamide
analogue
Radicicol
macrolactam
analogues

24. NEW RESEARCHES ON
MACROLIDE ANTIBIOTICS
• Based on the studies to date, the
macrolides such as azithromycin may offer
several advantages over most of the
macrolides, including:
1. Greater antimicrobial activity against
certain organisms;
2. Longer elimination half-life, thus allowing
less frequent administration; and
3. Lower incidence of adverse gastrointestinal
effects.

25. SPECTRUM OF ACTIVITY
Gram Positive Aerobes: Gram negative Aerobes
Erythromycin & Clarithromycin
display the best activity
Clarithro>Erythro>Azithro
Example:
▪
▪
▪
Stayphyloccous aureus
Streptococcus pneumoniae
Corynebacterium sp.
Newer macrolides such as-
Azithromycin has enhanced activity.
Azithro>Clarithro>Erythro
Example:
▪
▪
▪
H. influenzae
Neisseria sp.
Bordetella pertusis

26. Side effect
➢Headache
➢Taste disturbances
➢Stomatitis
➢Jaundice
➢Hepatitis
➢Mild gastric upset Abdominal pain
➢Dizziness
➢Glossitis
➢Cholestasis
➢Hearing problem