GA

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.