17) Macrolides:

Erythromycin, Azithromycin,
Roxithromycin, Clarithromycin
MACROLIDES
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.
Chemistry:
The macrolide antibiotics have three common
chemical characteristics:
(a) A large lactone ring (which prompted the name
macrolide),
(b) A ketone group, and
(c) A glycosidically linked amino sugar.
Usually, the lactone ring has 12, 14, or 16 atoms in
it, and it is often unsaturated, with an olefinic group
conjugated with the ketone function.
Erythromycin:
They may have, in addition to the amino sugar, a
neutral sugar that is linked glycosidically to the
lactone ring.
Because of the dimethylamino group on the sugar
moiety, the macrolides are bases that form salts
with pKa values between 6.0 and 9.0.
This feature has been used to make clinically useful
salts.
The free bases are only slightly soluble in water but
dissolve in somewhat polar organic solvents.
They are stable in aqueous solutions at or below RT
but are inactivated by acids, bases, and heat.
Mechanisms of Action and Resistance
It binds selectively to a specific site on the 50s
ribosomal subunit to prevent the translocation step
of bacterial protein synthesis.
It does not bind to mammalian ribosomes.
Broadly based, nonspecific resistance to the
antibacterial action of erythromycin among many
species of Gram-negative bacilli appears to be
largely related to the inability of the antibiotic
to penetrate the cell walls of these organisms.
 Erythromycin
D-
desosamine

L-cladinose
 IUPAC Name:

(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-
{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-
methyloxan-2-yl]oxy}-14-ethyl-7,12,13- trihydroxy-
4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyloxan-2-yl]oxy}-3,5,7,9,11,13-hexamethyl -
1-oxacyclotetradecane-2,10-dione
Physicochemical Properties:
The isolation of erythromycin, Erythrocin from
Streptomyces erythraeus.
Erythromycin is a very bitter, white or yellow-white,
crystalline powder.
It is soluble in alcohol and in the other common
organic solvents but only slightly soluble in water.
The free base has a pKa of 8.8; Saturated aq solns
develop an alkaline pH in the range of 8.0 to 10.5.
It is extremely unstable at a pH of 4 or below.
The optimum pH for stability of erythrornycin is at or
Pharmacokinetics & Dosage Forms:
Erythrornycin may be used as the free base in oral
dosage forms and for topical administration.
To overcome its bitterness and irregular oral
absorption (resulting from acid destruction and
adsorption onto food), various enteric-coated and
delayed-release dose forms have been developed.
Contd….

Erythromycin has been chemically modified with

primarily two different goals:
(a) to increase either its water or lipid solubility for
parenteral dosage forms &
(b) to increase its acid stability (and possibly its lipid
solubility) for improved oral absorption.

Erythromycin is widely distributed in the body, enters

cells and into abscesses, crosses serous membranes
and placenta, but not blood brain barrier.
Contd….

lt attains therapeutic concentration in the prostate.

It is 70-80% plasma protein bound, partly metabolized
and excreted primarily in bile in the active form.
Renal excretion is minor; dose need not be altered
in renal failure.
The plasma t 1/2 is 1.5 hr, but erythromycin persists
longer in tissues.

Preparations and dose:

Dose: 250-500 mg 6 hourly (max. 4 g/day), children
Biosynthesis of erythromycin by S. erythraea
The most widely used macrolide antibiotic,
Erythromycin A was first identified in the
fermentation products of a strain of
Saccharopolyspora erythraea (formerly known as
Streptomyces erythreus) isolated from a soil sample
from the Philippines.
The various aglycones (12-, 14-, and 16-monocyclic
lactones) are produced through polyketide
biosynthetic pathways.
Thus, many macrolides with their core lactones share
similar substituents and stereochemistry predicted
The biosynthesis of the macrolides can best be
illustrated by the synthesis of erythromycin A.
Erythromycin A is composed of a 14-membered
aglycone, to which are attached 6-deoxysugars, D-
desosamine at C-5, and L-cladinose at C-3.
The aglycone deoxyerythronolide (37) is assembled by
a polyketide synthase complex, deoxyerythronolide
B synthase (DEBS) encoded by the eryAI, eryAII, and
eryAIII genes corresponding to DEBS1, DEBS2, and
DEBS3, respectively.
After the completion of the synthesis of
deoxyerythronolide (37) by DEBS, it is hydroxylated
at C-6 by the P450 hydroxylase EryF to produce
erythronolide B (38).
Addition of L-mycarose by the gene products of the
EryB locus yields 3-α-mycarosylerythronolide B (39).
Subsequent addition of D-desosamine by EryC-
associated enzymes gives the first bioactive
macrolide in the biosynthetic pathway erythromycin
D (40).
Conversion of erythromycin D (40) to erythromycin A
is accomplished by two enzymatic actions:
(1) A P450 hydroxylase encoded by eryK gene
hydroxylates the C-12 of erythromycin D [to give
erythromycin C (41)] &
(2) An O-methyltransferase encoded by eryG gene
methylates the hydroxyl at C”-3 on the mycarose
moiety of erythromycin C [to yield erythromycin A
(20)].
Biosynthesis of erythromycin by S. erythraea
Contd….

{Methylation of the the hydroxyl gr. at C”-3 on the

mycarose moiety of erythromycin C [to yield
erythromycin A (20)] by An O-methyltransferase
Azithromycin
 Systematic IUPAC name

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-
trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-
11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-
hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl
2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-
hexopyranoside
Physicochemical Properties:
Azithromycin is derived from erythromycin; however, it
differs chemically from erythromycin in that a methyl-
substituted nitrogen atom is incorporated into the
lactone ring.
It is a prototype of a series of nitrogen-containing, 15
membered ring macrolides known as azalides.
Removal of the 9-keto group coupled with incorporation
of a weakly basic tertiary amine nitrogen function into
the macrolide ring increases the stability of
azithromycin to acid-catalyzed degradation.
These changes also increase the lipid solubility of the
molecule.
Pharmacokinetics:
The oral bioavailability of azithromycin is good, nearly
40%, provided the antibiotic is administered at least
1 hour before or 2 hours after a meal.
Food decreases its absorption by as much as 50%.
The pharmacokinetics of azithromycin are
characterized by rapid and extensive removal of the
drug from the plasma into the tissues followed by a
slow release.
Spectrum of Activity:
The spectrum of antimicrobial activity of azithromycin
similar to that observed for erythromycin and
clarithromycin but with some interesting differences.
In general, it is more active against Gram-negative
bacteria and less active against Gram-positive
bacteria than its close relatives.
The greater activity of azithromycin against H.
influenzae, M. catarrhalis, and M. pneumoniae
coupled with its extended half life permits a 5-day
dosing schedule for the treatment of respiratory tract
infections caused by these pathogens.
Roxithromycin
 Systematic (IUPAC) Name
(3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-6-
{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-
methyloxan-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-
{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-
dimethyloxan- 2-yl]oxy}-3,5,7,9,11,13-hexamethyl-
10-(2,4,7-trioxa-1-azaoctan-1-ylidene)-1-
oxacyclotetradecan-2-one
Properties:
It is a semisynthetic long-acting acid-stable macrolide
whose antimicrobial spectrum resembles closely
with that of erythromycin.
Pharmacokinetics:
Good enteral absorption and tissue penetration, an
average plasma t 1/2 of 12 hr making it suitable for
twice daily dosing, as well as better gastric
tolerability are its desirable features.
Spectrum of Activity:
Though its affinity for cytochrome P450 is lower, drug
interactions with terfenadine, cisapride and others
are not ruled out.
Thus, it is an alternative to erythromycin for
respiratory, ENT, skin and soft tissue and genital
tract infections with similar efficacy.

Dose:
150-300 mg BD 30 min before meals,
Children: 2.5-5 mg/kg BD.
Clarithromycin
 Systematic (IUPAC) Name

(3R,4S,5S,6R,7R,9R,11S,12R,13S,14S)-6-
{[(2S,3R,4S,6R) -4-(dimethylamino)-3-hydroxy-6-
methyloxan-2-yl]oxy} -14-ethyl-12,13-dihydroxy-4-
{[(2R,4S,5S,6S)-5-hydroxy -4-methoxy-4,6-
dimethyloxan-2-yl]oxy}-7 -methoxy-3,5,7,9,11,13-
hexamethyl -1-oxacyclotetradecane-2,10-dione
Physicochemical Properties:
Clarithromycin is a semi-synthetic macrolide
antibiotic.
A white to off-white crystalline powder. It is soluble in
acetone, slightly soluble in methanol, ethanol, and
acetonitrile, and practically insoluble in water.
Pharmacokinetics
Clarithromycin is rapidly absorbed from the
gastrointestinal tract after oral administration.
The absolute bioavailability of 250 mg clarithromycin
tablets was approximately 50%.
For a single 500 mg dose of clarithromycin, food
slightly delays the onset of clarithromycin
absorption, increasing the peak time from
approximately 2 to 2.5 hours.
Contd….

Peak plasma concentration attains within 2 to 3 hrs

after oral dosing.
The elimination T 1/2 is 5 to 7 hrs with 500 mg
administered every 8 to 12 hours.
The major metabolite found in urine is 14-OH
clarithromycin.
INDICATIONS AND USAGE
Gram-Positive Microorganisms
Staphylococcus aureus, Streptococcus pneumoniae,
Streptococcus pyogenes
Gram-Negative Microorganisms
Haemophilus influenzae, H. parainfluenzae
Moraxella catarrhalis
Other Microorganisms
Mycoplasma pneumoniaeChlamydophila
pneumoniae
Structure Activity
Relationships
The orientation of the sugars relative to the aglycone
macrolactone in erythromycin A is considered to be
important to ribosomal binding and hence
antibacterial activity.
The conformation of the erythronolide is therefore
important because of its influence on the
interaction of erythromycin A with the bacterial
ribosome.
Erythromycin A is acid labile, making it readily
susceptible to degradation in the stomach.
The acid-conversion products 8,9-
anhydroerythromycin-6,9-hemiketal (33) and
erythromycin-6,9;9,12-spiroketal (34) lack
antibacterial activity.
The initial erythromycin A acid-degradation product
(33) is formed by the intramolecular cyclization of
the 9-ketone and C-6-hydroxyl groups.