Antibiotics and Resistance: Key Concepts and Mechanisms

Bacteriostatic Vs Bactericidal

• Bacteriostatic Agents: Inhibit bacterial growth and reproduction.

• Examples:

  • Chloramphenicol
  • Erythromycin
  • Clindamycin
  • Sulfonamides
  • Trimethoprim
  • Tetracyclines

• Bactericidal Agents: Kill bacteria directly.

• Examples:

  • Aminoglycosides
  • Beta-lactams
  • Vancomycin
  • Quinolones
  • Rifampin
  • Metronidazole

Learning Objectives

• Understand types of antibiotics and how they function.
• Define and calculate therapeutic index of antibiotics.
• Describe the mechanism of action of Penicillin.
• Identify different methods for measuring antibiotic effectiveness:
  • Kirby-Bauer/disk diffusion test
  • E test (epsilometer)
  • Broth dilution test

Chemotherapy

• Chemotherapy Definition: Treatment of diseases using chemicals that target pathogens.
  • Types of Chemicals:
    • Antibiotics: Kill bacteria.
    • Antivirals: Inhibit viruses.
    • Antiprotozoans, Antihelminthics: Target eukaryotic parasites.
    • Anticancer drugs.

Key Concepts of Chemotherapy

• Target pathogens without harming host.
• Historical example: Arsenic used for syphilis treatment caused severe side effects.
• Exploit biological differences between host and pathogen:
  • Prokaryotic (70S) vs. Eukaryotic (80S) ribosomes.
  • Differences in cell wall structures (e.g., peptidoglycan in bacteria, chitin in fungi).

Antibiotics

• Penicillin:
• Discovered in 1928 by Alexander Fleming.
• Commercialized in 1940s; originally effective against Gram-positive bacteria.
• Sulfa Drugs:
• Discovered by Gerhard Domagk, effective in treating streptococcal infections.
• Sulfanilamide is key component derived from the dye Prontosil Red.

Enzyme Inhibition Mechanisms

1. Competitive Inhibition: Inhibitor competes with substrate for the active site.
2. Non-Competitive Inhibition: Inhibitor binds to an enzyme regardless of substrate presence.
3. Uncompetitive Inhibition: Inhibitor binds to the enzyme-substrate complex, preventing reaction.

Therapeutic Index

• Definition: Ratio of lethal dose (LD) to effective dose (ED).
  • Calculated as LD50/ED50.
  • Indicates safety margin of the drug.

Side Effects of Chemotherapy

• Potential adverse effects when targeting pathogens include:
  • Disruption of normal flora leading to yeast infections or C. difficile infections.
  • Inflammation from endotoxin release.

Limitations of Antibiotics

• Factors to Consider:
  • Location and concentration of the pathogen.
  • Intracellular pathogens and delivery challenges.
  • Areas with limited blood supply (e.g., blood-brain barrier).

Bacteriostatic vs. Bactericidal Revisited

• Key Difference: Bacteriostatic agents inhibit growth, while bactericidal agents kill bacteria.

Broad Spectrum vs. Narrow Spectrum Antibiotics

• Broad Spectrum: Effective against a wide range of bacteria.
• Narrow Spectrum: Target specific types of bacteria.

Measuring Antibiotic Effectiveness

• Kirby-Bauer: Disk diffusion method; measures efficacy through the size of the zone of clearance.
• E Test: Determines minimum inhibitory concentration (MIC) through a gradient diffusion.
• Broth Dilution Test: Serial dilution determines both MIC and MLC (minimum lethal concentration).

Antibiotic Resistance Mechanisms

1. Blocking Entry: Prevents drug from entering bacterial cell.
2. Inactivating Enzymes: Bacteria produce enzymes to deactivate antibiotics.
3. Alteration of Target Molecule: Changes the target site of the antibiotic.
4. Efflux: Pumps antibiotic out of the bacterial cell.

Resistance to Penicillin: Beta-lactamase

• Beta-lactamase: Enzymes that cleave the beta-lactam ring, rendering penicillin ineffective.

Modifications to Penicillin

• Variants developed for better absorption and effectiveness against different types of bacteria, including Gram-negative organisms.

Horizontal Gene Transfer (HGT)

• Mechanisms include conjugation, transformation, and phage transduction, contributing to the spread of antibiotic resistance among bacteria.

Environmental Impact on Antibiotic Resistance

• Sub-lethal doses of antibiotics can increase mutation rates and promote HGT, exacerbating resistance issues.

WHO Priority Pathogens for Antimicrobial Resistance

• Critical Group: Includes carbapenem-resistant Acinetobacter and Pseudomonas species; requires urgent research for new treatments.
• High Group: Includes vancomycin-resistant Enterococcus and methicillin-resistant Staphylococcus aureus.
• Medium Group: Includes penicillin-non-susceptible Streptococcus pneumoniae.

Future Directions

• Research into new antibiotics from environmental sources to combat emerging resistance.