ROLL NO: 3-05-09-0926

Antibiotics are the secondary metabolites secreted by a microorganism which inhibits

other microorganism. They can be classified as bacteriostatic if they inhibit the growth of the microorganism and bactericidal if they kill it. On the basis of their spectrum of pathogens, they are categorized as: 1) Broad spectrum- if they have a broader range of pathogens, exampleChloramphenicol and, 2) Narrow spectrum- if they have a narrow range of pathogens, example- Penicillin.

Antibiotics have various targets in a bacterial cell. They are as follows:

1) Cell Wall- Drugs like Vancomycin, Cephalosporin,Penicillin,interfere with the cell wall biosynthesis of microorganisms. 2) DNA synthesis- Metronidazole inhibits DNA synthesis of the bacteria while drugs like Quinolones inhibit the activity of the enzyme,DNA Gyrase which is concerned with DNA replication. 3) RNA Polymerase- This enzyme helps in the transcription of DNA to form mRNA and is inhibited by Rifampicin. 4) Phospholipid membrane- Polymixins interfere with cell membrane biosynthesis. 5) Protein synthesis- The organelle ribosome is targeted to block protein synthesis in bacteria. Drugs like Erythromycin,Chloramphenicol inhibit the 50S subunit of the ribosome while Tetracyclins and Streptomycins block the 50S subunit which blocks translation and protein synthesis.

However,there has been increasing concern for the design of new and modified antibiotics because of the increasing drug resistance acquired by bacteria which renders the antibiotic non-functional. Bacteria acquire resistance by either mutating its existing genes or by acquiring genes from other resistant bacteria via plasmids by means of which it can shield itself from antibiotic action.

The following figure gives a brief overview of the various mechanisms by which bacteria acquire resistance.

The various resistance mechanisms in bacteria are as follows: 1. Synthesis of enzymes that breakdown the antibiotic- Penicillanase, cephalosporinase. 2. Modification of their own enzymes that would be the antibiotic target- DNA Gyrase. 3. Synthesis of efflux pumps sequestered into the cell that would flush out the antibiotic to the outside of the cell- Aminoglcosides. 4. Modification of the antibiotic target- Erythromycin. 5. Modification of the antibiotic itself- Kanamycin

Ribosome: A potent target

Ribosomes are protein synthesizing machinery present in both prokaryotes and eukaryotes. Both prokaryotic and eukaryotic ribosomes have conserved structural features but many evolutionary differences exist which can be exploited as potential drug development targets. Ribosomes in prokaryotes consist of two subunits: The large subunit or 50S and the smaller subunit or 30S. 50S subunit is affected by Macrolides (erythromycin,streptomycin),Lincosamides. 30S subunit is affected by Aminoglycosides (streptomycin,kanamycin), Aminocyclitols(spectinomycin). The subunit interactions is affected by Oxalidinones(linezolid). Earlier studies were made to study drug-ribosome interactions and it was based on characterising resistance mutations in the genes of ribosomal components and crosslinking of drug to ribosome or footprinting. It was observed that most of the sites of antibiotic action coincide with functional centres of ribosome.

The various functional centres identified in the ribosome are: 1. 2. 3. 4. 5. The tRNA binding sites in the 30S subunit. The GTPase-activating region in the 50S subunit. The Decoding centre in the 30S subunit. Peptidyl Transferase centre. Nascent peptide exit tunnel.

The following figure gives an idea about inhibition of protein synthesis by antibiotics.

Hence, understanding the mechanism of action of various drugs becomes important for the design of new drugs for clinical purpose and also to understand the mode of resistance acquired by the host cells to different antibiotics.

References: Microreview paper by Tanel Tenson and Alexander Mankin, {2006} Blackwell Publishing Ltd. Molecular Microbiology

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