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)