Macrolides - Medicinal Chemistry III B. Pharma 6th Semester

MACROLIDES

Contents

• Macrolides - Introduction

• Chemistry of Macrolides

• Over view of Mechanism of action and Resistance of Macrolides

• Spectrum of Activity of Macrolides

• Study of Individual products

Learning Objectives

At the end of this lecture, student will be able to

• Discuss the chemistry of Macrolides

• Explain the mode of action and resistance of Macrolides

• Outline the spectrum of activity of Macrolides

• Discuss the structural features of Macrolides and uses

Introduction

• Macrolides are the antibiotics isolated from the Actinomycetes.

• Picromycin is the first compound of this group identified as ‘Macrolide’.

• Others in the sequence are erythromycin and carbomycin and then other macrolides like azithromycin, clarothromycin and oleandomycin.

Chemistry

3 common chemical characteristics

• A large lactone ring (i.e., why the name macrolide)

• A ketone group

• A glycosidically linked amino sugar

• 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.

• In addition, to the amino sugar, a neutral sugar that is linked glycosidically to the lactone ring may be present eg., Erythromycin

• They are stable in aqueous solutions at or below room temperature but are inactivated by acids, bases and heat.

• Macrolides are bases that form salts with pKa values between 6.0 and 9.0, because of the dimethyl amino group on the sugar moiety.

PICROMYCIN

ERYTHROMYCIN

Mechanism of action

Bacteriostatic

• It binds selectively to specific site on the 50S ribosomal subunit to prevent the translocation step of bacterial protein synthesis

• It does not bind to mammalian ribosomes and so will not affect the protein synthesis in mammalian cells

Mechanism of Resistance

• The nonspecific resistance to the antibacterial action of erythromycin among many species of Gram-ve bacilli is largely related to the inability of the antibiotic to penetrate the cell walls of these organisms. Protoplasts from Gram –Ve bacilli which lack cell walls are sensitive to erythromycin.

• A highly specific resistance mechanism to the macrolide antibiotics occurs in erythromycin-resistant strains of S.aureus. These strains produce an enzyme that methylates a specific residue at the erythromycin-binding site of the bacterial 50S ribosomal subunit. The methylated ribisomal RNA remains active in protein synthesis but no longer binds erythromycin.

Spectrum of activity

The spectrum of antibacterial activity of the more potent macrolides, as erythromycin resembles that of penicillin.

They are active against bacterial strains that are resistant to the penicillins

Effective against most species of Gram+ve bacteria-both cocci & bacilli, some Gram-ve cocci especially Neisseria species, Treponema pallidum, etc.

In contrast to penicillins, they are effective against Mycoplasma, Chlamydia, Campylobacter and Legionella species, some strains of H. influenzae and Brucella species.

Erythromycin

Isolated from S.erythraceus

• It is a well-tolerated antibiotic

• Used in the treatment of upper respiratory and soft-tissue infections caused by Gram+ve bacteria.

• Effective against many venereal diseases including gonorrhea and syphilis

• Useful alternative for the treatment of many infections in patients allergic to penicillins.

• Erythromycin was shown to be effective therapy for Eaton agent pneumonia (Mycoplasma pneumoniae), venereal diseases caused by Chlamydia, bacterial enteritis caused by Campylobacter jejuni, and Legionnaires disease

Clarithromycin