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:-

Site of action

Antibiotic

Process interrupted

Type of activity

1

Cell wall

Penicillins

Cephalosprins

Cycloserine

Vancomycin

Bacitracin

Cell-wall cross linking

Cell-wall cross linking

Synthesis of Cell wall peptides

Muco-peptide synthesis

Muco-peptide synthesis

Bactericidal

Bactericidal

Bactericidal

Bactericidal

Bactericidal

2

Cell membrane

Amphotericin B

Nystatin

Polymyxins

Membrane function

Membrane function

Membrane Integrity 

Fungicidal

Fungicidal

Bactericidal

3

Ribosomes

Chloramphenicol

Protein synthesis

Bactericidal

50 S subunit

Erythromycin

Lincomycins

Protein synthesis

Protein synthesis

Bactericidal

Bactericidal

30 S subunit

Aminoglycosides

Tetracyclines

Protein synthesis & fidelity

Protein synthesis

Bactericidal

Bacteriostatic

4

Nucleic Acids

Actinomycin

Griseofulvin

DNA & mRNA synthesis

Cell division, microtubule Assembly

Pancidal

Fungicidal

DNA and /or RNA

Mitomycin

Rifampin

DNA synthesis

 mRNA synthesis

Pancidal

Bactericidal


“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)


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