Lincomycins & Polypeptides – Medicinal Chemistry III B. Pharma 6th Semester

Lincomycins & Polypeptides

Contents

• Mechanism of action of Lincomycins

• Study of Individual Lincomycins

• Structures of lincomycin and clindamycin

• Clinical uses of lincomycin and clindamycin

• Polypeptides – Introduction

• Mechanism of action of Polypeptides

Learning
Objectives

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

• Draw the structures of lincomycin and clindamycin

• List clinical applications of lincomycin and clindamycin

• Explain the mechanism of action of Lincomycins and
Polypeptides

• Discuss the structural features and uses of individual
compounds

Introduction

• Lincomycins are sulfur-containing antibiotics isolated
from Streptomyces lincolnensis

• Lincomycin is the most active and medically useful of the
compounds obtained from fermentation

• Clindamycin appears to have the greater antibacterial
potency and better pharmacokinetic properties

• Lincomycins resemble macrolides in antibacterial spectrum
and biochemical mechanisms of action

• They are primarily active against Gram positive bacteria
cocci but are also effective against non–spore-forming anaerobic bacteria
actinomycetes, mycoplasma and some species of plasmodium

• Food does not interfere with the absorption. Hence it is
completely absorbed after oral administration

Mechanism
of Action and Resistance 

• Lincomycin inhibits protein synthesis in susceptible
bacteria by binding to the 50S ribosomal subunit of bacterial ribosomes and
preventing peptide bond formation upon transcription.

• It is usually considered bacteriostatic, but may be
bactericidal in high concentrations or when used against highly susceptible
organisms

• A pattern of bacterial resistance and cross-resistance
similar to that observed with the macrolides is seen

Distribution

• Approximately 90% of the antibiotic is plasma bound

• They penetrate most tissues well,including bone

• Hence bone and joint infections caused by suscepitible
organisms respond well to treatment with clindamycin

List of
Compounds 

• Lincomycin

• Clindamycin

Lincomycin 

• The structure contains a basic function -the pyrrolidine
nitrogen

• Lincomycin is used for the treatment of infections caused
by Gram- positive organisms-Staphylococci, hemolytic streptococci, and
pneumococci

• It is absorbed moderately well orally and distributed
widely in the tissues

• Effective concentrations are achieved in bone for the
treatment of staphylococcal osteomyelitis

• But not in the cerebrospinal fluid for the treatment of
meningitis

Toxicity:-

• Allergy (rash), occasional gastrointestinal complaints
(nausea, vomiting & diarrhea)

• In certain cases – diarrhea & development of
pseudomembranous colitis (inflammation of the colon)

Clindamycin
Hydrochloride

• Replacement of 7(R)-OH group with 7(S)-Chloro   group  
has increased antibacterial activity & improved absorption

• Clindamycin is recommended for the treatment of a wide
variety of upper respiratory, skin, and tissue infections caused by susceptible
bacteria

• It is reserved for tissue staphylococcal infections in
penicillin-allergic patients & for severe anaerobic infections outside the
CNS

• Ordinarily it should not be used to treat respiratory
tract infections caused by bacteria sensitive to safer antibiotics or for
phophylaxis

Toxicity:-

• Same as lincomycin.

• Clindamycin (or lincomycin) – associated colitis may be
particularly dangerous in elderly or debilitated patients and has caused deaths
in such individuals.

Polypeptides

• Among the most powerful bactericidal antibiotics

• Possess a polypeptide structure

• Their clinical use has been limited due to undesirable side
reactions, particularly renal toxicity.

• Other limitation – lack of systemic activity following
oral administration.

Polypeptide antibiotics possess unique characteristics

1. Consists of several structurally similar but chemically
distinct entities isolated from a single source.

2. Most of them are cyclic with a few exceptions eg.,
Gramicidin

3. Contain D-Aminoacids &/of ‘Unnatural’ aminoacids not
found in higher plants or animals

4. Many of them contain non-amino acid moieties such as
heterocycles, fatty acids, sugars etc.

5. May be acidic, basic, zwitter ionic or neutral depending
on the number of free carboxyl & amino or guanidino groups in their
structures.

Mechanism of action:-

• These polypeptide antibiotics differ widely in their
mechanism of action & antimicrobial properties.

Unclassified
Antibiotics

Chloramphenicol:-

• Widely used broad-spectrum antibiotic

• Isolated from Streptomyces venejuelae.

Use:-

• In the treatment of serious infections caused by strains
of gram +ve and gram –ve bacteria

• As alternative therapy for meningitis.

• In rickettsial infections such as Rocky Mountain Spotted
fever.

Synthesis of
Chloramphenicol:

Novobiocin:-

• Isolated from Streptomyces spp.

• Bacteriostatic.

• Used in the treatment of Staphyloccocal infections
resistant to other antibiotics and sulfas and for patients allergic to these
drugs.

• Adverse reactions: – Urticaria (Nettle rash), Allergic
rashes

• Hepatotoxicity & Blood dyscrasias.