ANTIMICROBIAL AGENTS

Question 1

The fact that a microorganism is capable of destroying one of another species (antibiosis) was established in the latter half of the 19th century when Louis Pasteur and Robert Kock noted the antagonistic effect of other bacteria on the anthrax organism and pointed out that this action might be put to therapeutic use.

Question 2

Classification of Antibiotics Based on Chemical/Biosynthetic Origin
Which are natural, semi synthetic & synthetic

Answer 2

Penicillin –N
Amoxicilin –SS
Sulfinamide –S

Question 3

Based on Biological Activity

Answer 3

Bactericidal: Antibiotics that kill bacteria. Example: Penicillin, Aminoglycosides.

Bacteriostatic: Antibiotics that inhibit the growth of bacteria. Example: Tetracyclines, Erythromycin.

Question 4

Based on range of action

Answer 4

Narrow: Penicillin affects +ve
Broad: Tetracycline

Question 5

Based on Site of Action

Which are

Cell Wall Inhibitors
Protein Synthesis Inhibitors
Anti-metabolites
Nucleic Acid Inhibitors

Answer 5

Cell Wall Inhibitors: Prevent the synthesis of bacterial cell walls. Example: Penicillins, Cephalosporins.

Protein Synthesis Inhibitors: Disrupt bacterial protein synthesis. Example: Aminoglycosides, Tetracyclines.

Anti-metabolites: Interfere with bacterial metabolism. Example: Sulfonamides.

Nucleic Acid Inhibitors: Inhibit DNA or RNA synthesis. Example: Fluoroquinolones.

Question 6

Bacteriostatic Antibiotics
Function: Inhibit the growth of bacteria, but do not kill them outright.

Dependence: The body’s immune system must eliminate the bacteria.

Usage: These require sufficient treatment duration to allow the immune system to work.

Examples:

• Tetracyclines: Inhibit protein synthesis.
• Erythromycin: Also inhibits protein synthesis.
• Sulfonamides: Inhibit folic acid synthesis.
• Chloramphenicol: Inhibits protein synthesis.

Bactericidal Antibiotics
Function: Kill bacteria directly.

Importance: Essential for treating severe infections where the immune system alone cannot clear the infection.

Usage: Crucial for infections in areas like the heart (endocardium) or brain (meninges), where immune defenses are less effective.

Examples:
- Aminoglycosides: Cause misreading of mRNA.
- Fluoroquinolones: Inhibit DNA gyrase and topoisomerase IV.
- Penicillins: Inhibit cell wall synthesis.
- Cephalosporins: Also inhibit cell wall synthesis.

Question 7

Modes of Action of Inhibitors of Cell Wall Synthesis
Mechanism of Action

Binds to Penicillin-Binding Proteins (PBPs): These are enzymes found in the bacterial cell membrane that help in the construction of the cell wall.
Inhibits Cell Wall Synthesis: Prevents the bacteria from forming a strong cell wall, which is crucial for their survival.

Enzymatic Autolysis: Once the cell wall synthesis is inhibited, enzymes called autolysins break down the cell wall.

Cell Lysis: High internal osmotic pressure causes the cell to burst due to the weakened or damaged cell wall.

Question 8

Inhibitors of cell wall synthesis work by targeting the mechanisms bacteria use to build and maintain their cell walls. By binding to penicillin-binding proteins, these drugs prevent the proper formation of the cell wall, leading to bacterial cell death due to osmotic pressure. The main classes include beta-lactams (penicillins and cephalosporins), glycopeptides, and bacitracin. Each class has specific examples with varying spectrums of activity and resistance to bacterial enzymes.

Question 9

beta-lactams (penicillins and cephalosporins),

Question 10

List examples of Penicillinase-Resistant Penicillins

Answer 10

• Methicillin
• Isoxazolyl Penicillins: Cloxacillin, Flucloxacillin, Oxacillin (resistant to bacterial enzymes that destroy penicillin).

Question 11

List the Aminopenicillins: & which is broadest?

Answer 11

Ampicillin
Amoxicillin
Bacampicillin (broader spectrum of activity).

Question 12

Cephalosporins
Origin: Isolated from the mold Cephalosporium.

Generations: There are five generations, each with a broader spectrum of activity and increased resistance to bacterial enzymes.

List the 5 please

Answer 12

1st Generation: Cephalothin, Cephradine.

2nd Generation: Cefuroxime, Cefoxitin.

3rd Generation: Cefotaxime (Claforan), Ceftriaxone (Rocephin), Ceftazidime (Fortum), Cefoperazone, Cefixime.

4th Generation: Cefepime.

5th Generation: Ceftaroline, Ceftobiprole.

Question 13

Inhibitors of Cell Wall Synthesis: Glycopeptides and Bacitracin

Answer 13

Glycopeptides: These antibiotics, such as vancomycin, inhibit cell wall synthesis by binding to the precursors of cell wall synthesis and preventing them from being incorporated into the cell wall.

Bacitracin: This antibiotic interferes with the transport of cell wall precursors across the cell membrane, which is essential for cell wall synthesis.

Question 14

Interruption of Protein Synthesis
Overview
Antibiotics can interfere with bacterial protein synthesis by targeting the ribosomal machinery that the bacteria use to make proteins. This interruption can occur at different stages of protein synthesis:

Inhibit the initiation of Protein Synthesis: Prevent the start of protein synthesis.
Inhibit the Elongation Process: Stop the addition of amino acids to the growing protein chain.

Question 15

Antibiotics that disrupt protein synthesis target the bacterial ribosomes, essential machinery for making proteins.
By binding to the 30S ribosomal subunit, aminoglycosides prevent the initiation and elongation of protein synthesis, effectively killing the bacteria. This class of antibiotics is particularly effective against gram-negative bacteria but not against anaerobic or intracellular bacteria. They often work better when combined with ß-lactam antibiotics, which help increase their uptake by bacteria.

Question 16

Synthetic analogue of Tetracycline. Is?

Answer 16

Tigecycline

Description: Synthetic analogue of Tetracycline.

Spectrum of Activity: Broad spectrum; effective against strains resistant to tetracyclines and other antibiotics, but not against Pseudomonas.

Clinical Use: Used for skin and soft tissue infections, and intra-abdominal infections.

Question 17

Summary

Tetracyclines:

Action: Bind to the 30S ribosome, inhibit aminoacyl-tRNA binding.

Use: Broad spectrum, intracellular bacteria.

Issues: Poor absorption with certain foods, common resistance, potential adverse effects on teeth and bones.

Glycylcyclines:

Action: Similar to tetracyclines but broader spectrum and effective against resistant strains.

Use: Skin, soft tissue, and intra-abdominal infections.

Note: Not effective against Pseudomonas.

Spectinomycin:

Action: Interferes with mRNA and 30S ribosome interaction without misreading mRNA.

Use: Treats penicillin-resistant Neisseria gonorrhoeae.

Note: Resistance is common.

Oxazolidinones:

Action: Inhibit formation of N-formylmethionyl-tRNA at the 30S ribosome.

Use: Effective mainly against Gram-positive bacteria.

Question 18

Beta-Lactams
Includes: Penicillins, Cephalosporins, Carbapenems, Monobactams.
Structure: All beta-lactams have a core structure called the penicillanoic acid backbone.
Function: They inhibit cell wall synthesis by binding to penicillin-binding proteins (PBPs), leading to cell wall autolysis and bacterial death.

Question 19

Aminoglycosides
Examples: Gentamicin, Amikacin, Kanamycin.
Structure: Aminoglycosides contain amino sugars linked by glycosidic bonds.
Function: They irreversibly bind to the 30S ribosomal subunit, inhibiting protein synthesis and leading to bacterial death.

Question 20

Quinolones
Examples: Nalidixic acid, Cinoxacin, Ciprofloxacin, Ofloxacin, Levofloxacin.
Structure: Quinolones have a bicyclic core structure.
Function: They inhibit DNA gyrase and topoisomerase IV, which are essential for DNA replication. This inhibition causes DNA supercoiling relaxation, halting chromosomal replication, and leading to cell death.

Question 21

Macrolides
Examples: Erythromycin, Spiramycin, Clarithromycin, Dirithromycin, Azithromycin.
Structure: Macrolides feature a macrocyclic lactone ring attached to two sugars (desosamine and cladinose).
Function: They bind reversibly to the 50S ribosomal subunit, inhibiting RNA-dependent protein synthesis in bacteria.

Question 22

Tetracyclines
Examples: Tetracycline, Chlortetracycline, Oxytetracycline, Demeclocycline, Doxycycline, Minocycline.
Structure: Tetracyclines have a hydronaphthacene nucleus composed of four fused rings.
Function: They bind to the 30S ribosomal subunit, preventing the attachment of aminoacyl-tRNA, thereby inhibiting peptide synthesis

Question 23

Lincosamides
Examples: Lincomycin, Clindamycin.
Structure: Lincosamides consist of an amino acid linked to an amino sugar.
Function: They bind to the 50S ribosomal subunit, interfering with peptidyl transfer and preventing peptide chain elongation, thus suppressing protein synthesis. Depending on the concentration, they can be bactericidal or bacteriostatic.

Question 24

Glycopeptides and Lipopeptides
Glycopeptides: Vancomycin, Teicoplanin.
Lipopeptides: Daptomycin; Ramoplanin (a lipoglycopeptide).
Structure: Glycopeptides have large glycosylated cyclic or polycyclic nonribosomal peptides, whereas lipopeptides contain lipid moieties.
Function:
Glycopeptides: Inhibit peptidoglycan synthesis by binding to the D-alanyl-D-alanine portion of the cell wall precursors.
Lipopeptides: Disrupt cell membrane function by interfering with the transport of cell wall precursors, leading to cell death.

Question 25

Summary
Each antibiotic class has unique structural features and mechanisms of action:

Beta-Lactams: Inhibit cell wall synthesis.
Aminoglycosides: Irreversibly bind to the 30S ribosome, inhibiting protein synthesis.
Quinolones: Inhibit DNA gyrase and topoisomerase IV, disrupting DNA replication.
Macrolides: Bind to the 50S ribosome, inhibiting protein synthesis.
Tetracyclines: Bind to the 30S ribosome, preventing peptide synthesis.
Lincosamides: Bind to the 50S ribosome, preventing peptide chain elongation.
Glycopeptides and Lipopeptides: Inhibit peptidoglycan synthesis and disrupt cell membrane function.

Question 26

Summary
Sulfonamides and Trimethoprim: Interfere with bacterial folic acid synthesis, often used together for a synergistic effect.
Streptogramins: Inhibit protein synthesis through the 50S ribosomal subunit, effective in a synergistic manner.
Oxazolidinones: Prevent initiation of protein synthesis.
Polypeptides: Disrupt bacterial cell membranes leading to cell death.
Chloramphenicol: Inhibits protein synthesis, bacteriostatic but can be bactericidal against some pathogens.
Nitrofurans: Inhibit bacterial enzymes and damage DNA, used for UTIs.
Metronidazole: Disrupts DNA, used against anaerobic bacteria and protozoa.
Rifampin: Inhibits RNA synthesis, mainly used for TB.
Broad Spectrum Antibiotics: Effective against a wide range of bacteria.
Narrow Spectrum Antibiotics: Effective against specific types of bacteria.

Question 27

• Chemical Structure: Both have structures similar to para-aminobenzoic acid (PABA).
• Mechanism of Action:
  
  • Trimethoprim: A pyrimidine analog that inhibits the enzyme dihydrofolate reductase, which is crucial for bacterial folic acid synthesis.
  • Sulfonamides: Block the enzyme pteridine synthetase, also interfering with folic acid synthesis.
• Combination Therapy: When combined (e.g., trimethoprim-sulfamethoxazole or TMP-SMX), they potentiate each other’s effects, making them more effective in inhibiting bacterial growth.

• Mechanism of Action:
  
  • Group A Streptogramins: Cause conformational changes that increase the affinity of Group B Streptogramins for the 50S ribosomal subunit.
  • Group B Streptogramins: Cause the release of incomplete peptide chains from the 50S ribosomal subunit.
• Effect: Synergistic bactericidal effect by inhibiting protein synthesis through the 50S ribosomal subunit.

• Mechanism of Action: Prevent the initiation of translation in protein synthesis by preventing the formation of a functional initiation complex (tRNA, mRNA, and the ribosome), binding through the 50S subunit.

• Mechanism of Action: Interact with phospholipids in the bacterial cell membrane, increasing cell permeability and disrupting osmotic integrity, leading to cell leakage and death.

• Chemical Structure: Contains a nitrobenzene ring.
• Mechanism of Action: Binds reversibly to the peptidyltransferase component of the 50S ribosomal subunit, preventing chain elongation.
• Effect: Bacteriostatic, but can be bactericidal against some pathogens at therapeutic concentrations.

• Chemical Structure: A nitro group joined to a heterocyclic ring.
• Mechanism of Action: Though not precisely known, it is believed to inhibit various bacterial enzymes and damage DNA.
• Use: Primarily for treating urinary tract infections.

• Chemical Structure: A 5-nitroimidazole derivative.
• Mechanism of Action: Produces short-lived, highly cytotoxic intermediate compounds or free radicals that disrupt bacterial DNA.
• Use: Effective against anaerobic bacteria and some protozoal infections.

• Chemical Structure: A semi-synthetic antibiotic derived from rifamycin B.
• Mechanism of Action: Forms a stable complex with bacterial DNA-dependent RNA polymerase, preventing the initiation of DNA transcription.
• Use: Primarily used for treating tuberculosis.

• Definition: Effective against a wide range of organisms, including both gram-negative and gram-positive bacteria.
• Examples: Tetracyclines, chloramphenicol, some cephalosporins.

• Definition: Effective against specific types of bacteria.
• Examples: Monobactams, isoniazid.

1. Sulfonamides and Trimethoprim: Interfere with bacterial folic acid synthesis, often used together for a synergistic effect.
2. Streptogramins: Inhibit protein synthesis through the 50S ribosomal subunit, effective in a synergistic manner.
3. Oxazolidinones: Prevent initiation of protein synthesis.
4. Polypeptides: Disrupt bacterial cell membranes leading to cell death.
5. Chloramphenicol: Inhibits protein synthesis, bacteriostatic but can be bactericidal against some pathogens.
6. Nitrofurans: Inhibit bacterial enzymes and damage DNA, used for UTIs.
7. Metronidazole: Disrupts DNA, used against anaerobic bacteria and protozoa.
8. Rifampin: Inhibits RNA synthesis, mainly used for TB.
9. Broad Spectrum Antibiotics: Effective against a wide range of bacteria.
10. Narrow Spectrum Antibiotics: Effective against specific types of bacteria.

This comprehensive understanding helps in choosing the appropriate antibiotic based on the infection type and the specific pathogen involved.