Antibiotics – Medicinal Chemistry III B. Pharma 6th Semester

Antibiotics

Contents

•       History
& Introduction

•       Commercial
Production of antibiotics

•       Over
view of Mechanism of action of various antibiotics

•       Various
methods of Classification of Antibiotics

Learning Objectives

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

Understand the history of evolution of antibiotics as
therapeutic agents

Define the term “antibiotic”

Explain how antibiotics are commercially produced

Explain the general mode of action of various antibiotics

Classify antibiotics based on various criteria

History: Modern Antibiotic era

•      
Initiated  by the accidental discovery of the
anti-bacterial properties of Penicillin in 1929 by Sir Alexander Fleming

•      
Florey
and Chain introduced Penicillin into therapy [1938]

•      
Definition
(original) [By WAKSMAN (1942)]

•      
“ An
antibiotic or antibiotic substance is a substance produced by micro-organisms,
which has the capacity of inhibiting the growth and even of destroying other
micro-organisms”

Modern Definition:

•       “
Any substance produced by a living organism that is capable of inhibiting the
growth or survival of one or more species of micro-organisms in low
concentrations”

•       Modified
by Medicinal Chemists to include the substances obtained from natural,
semi-synthetic and synthetic sources

Hence a substance is classified as an antibiotic if the
following conditions are met:

•       It
is a product of metabolism

•       It
is a synthetic product produced as a structural analogue of a naturally
occurring antibiotic

•       It
antagonizes the growth or survival of one or more species of micro-organisms

•       It
is effective in low-concentrations

Commercial Production of antibiotics

The general scheme of commercial production of antibiotics
for medicinal use may be divided into six steps:

•       Preparation
of a pure culture of the desired organism for inoculation of the fermentation
medium.

•       Fermentation,
during which the antibiotic is formed.

•       Isolation
of the antibiotic from the medium

•       Purification

•       Assays
for potency, sterility, absence of pyrogens and other necessary data

•       Formulation
into acceptable and stable dosage forms.

MECHANISM OF ACTION

•       Mechanisms
of action of some common antibiotics are as follows:-

“ANTIBIOTICS THAT INTERFERE WITH THE METABOLIC SYSTEMS FOUND IN MICRO-ORGANISMS
AND NOT IN MAMALIAN CELLS ARE THE MOST SUCCESSFUL ANTI-INFECTIVE AGENTS”

For example,

•       Antibiotics
that interfere with the synthesis of bacterial cell walls have a high potential
for selective toxicity.

ü  Cycloserine
is an antimetabolite of D-Alanine, a constituent of bacterial cell wall.

ü  Many
antibiotics like aminoglycosides, tetracyclines etc selectively interfere with
microbial protein synthesis or nucleic acid synthesis like Rifampin.

ü  Others
like polymixins and polyenes, interfere with the integrity and function of
microbial cell membranes.

•       The
agents may be a bactericidal or a bacteriostatic.

•       This
distinction is important for the treatment of serious, life-threatening
infections, particularly if the natural defense mechanisms of the host are
either deficient or overwhelmed by the infection – in such cases, a
bactericidal is indicated.

Classification of Antibiotics

Various criteria are used to classify ‘Antibiotics’

I method: Based
on the clinical effectiveness, spectrum of activity and degree of selectivity.

Class 1:- Those
inhibiting only one group of micro-organisms

•       “Narrow
Spectrum Antibiotics” eg. Nystatin and Bacitracin.

•       Exhibit
a high degree of selectivity.

Class 2:- Those
inhibit both “Gram +Ve” and “Gram -Ve” bacterial and /or other intracellular
organisms.

•       “Broad
Spectrum Antibiotics” eg. Chloramphenicol and Tetracyclin.

II method:
based on the sources from which antibiotics are obtained. They can be
classified as

a. Natural:-
obtained from the large scale fermentation of micro-organisms.

     Eg. ‘Bacitracin’
and ‘Polymixin’ are obtained from some bacilli.

     ‘Streptomycin’
and ‘Tetracycline’ are obtained from streptomyces species

b. Semi-synthetic:-
The precursors of these antibiotics are obtained from natural source. Synthetic
method is utilized to produce the analogues/derivatives of these precursors.

For example: 6-Aminopenicillanic acid is obtained from the
cultures of P. Chrysogenum. During the commercial production of benzyl
penicillin (Penicillin G), Phenyl acetic acid is added to the medium in order
to get the product.

c. Synthetic:-
This class includes antibiotics which are having purely synthetic origin.

•       For
example: Chloramphenicol (a broad spectrum antibiotic), ciprofloxacin,etc

III method: based
on the differences in the mechanism of action.

A.     
Drugs that interferes with the biosynthesis
of bacterial cell-wall

   Eg. Penicillins,
Cephalosprins, Cycloserin, Bacitracin & Vancomycin.

B.     
Drugs that interfere in the functioning of
Cytoplasmic membrane.

   Eg. Polymixins,
Aphotericin B and Nystatin.

C.     
Drugs that interfere with the protein
biosynthesis.

   Eg. Erythromycin,
Lincomycins, Tetracyclines and Chloramphenicol.

D.     
Drugs that interfere with  Nucleic acid biosynthesis

   Eg. Actinomycin,
Griseofulvin and Rifampin.

IV method: based
on the chemical structure.

ü  Β-lactam
Antibiotics:

     Eg. Penicillins,
Cephalosprins, Monobactams.

ü  Aminoglycosides:

     Eg. Kanamycin,
Streptomycin, Gentamycin, Neomycin, etc.

ü  Tetracycline
Antibiotics:

      Eg.
Tetracycline, Chlortetracycline, Oxytetracycline, etc.

ü  Peptide
Antibiotics:

     Eg. Amphomycin,
Tyrothricin, Bacitracin, etc.

ü  Macrolide
Antibiotics:

     Eg. Erythromycin,
Oleandomycin

ü  Lincomycin:

     Eg. Lincomycin,
Clindamycin, pirlimycin

ü  Unclassified
Antibiotics:

     Eg.
Chloramphenicol, Rifamycin.

q  “Anti-fungal
Antibiotics”

     Eg. Griseofulvin,
Polyene Antibiotics (Amphotericin B, Nystatin, Candicidin)