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.
|
Polypeptide |
Mechanism |
Activity |
|
1. Bacitracin & Vancomycin |
Interfere with bacterial cell wall synthesis |
Effective only against Gram+ve bacteria |
|
2. Gramicidins & the |
Interfere with cell membrane functions in bacteria |
Gramicidins-effective only against Gram+ve bacteria Polymyxins-are effective only against Gram-ve species |
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.