Unit Two Study Guide: Chapter 20 - Antimicrobial Drugs and Antimicrobial Drugs

Historical Foundations of Chemotherapy

• Paul Ehrlich: Coined the term "chemotherapy." He was a pioneer in seeking a "magic bullet" that would destroy pathogens without harming the host.
• Alexander Fleming: Credited with the discovery of penicillin, the first antibiotic, derived from the mold Penicillium.

Microbes as Sources of Antibiotics

More than half of all current antibiotics are produced by a specific genus of bacteria known as Streptomyces. Below are the representative sources of antibiotics categorized by their biological origin:

• Gram-Positive Rods:
  • Bacillus subtilis: Produces Bacitracin.
  • Paenibacillus polymyxa: Produces Polymyxin.
• Actinomycetes (Specifically Streptomyces and related genera):
  • Streptomyces nodosus: Produces Amphotericin B.
  • Streptomyces venezuelae: Produces Chloramphenicol.
  • Streptomyces aureofaciens: Produces Chlortetracycline and Tetracycline.
  • Saccharopolyspora erythraea: Produces Erythromycin.
  • Streptomyces fradiae: Produces Neomycin.
  • Streptomyces griseus: Produces Streptomycin.
  • Micromonospora purpurea: Produces Gentamicin.
• Fungi:
  • Cephalosporium spp.: Produces Cephalothin.
  • Penicillium griseofulvum: Produces Griseofulvin.
  • Penicillium chrysogenum: Produces Penicillin.

Challenges and Principles of Antimicrobial Therapy

• Challenges of Eukaryotic and Viral Infections:
  • Fungal, Protozoan, and Helminthic Infections: Because these are caused by eukaryotic cells, they are structures and metabolisms very similar to human cells. This similarity makes it difficult to find targets in these pathogens that do not also target the host cells.
  • Viral Infections: Viruses are obligately intracellular; they live within the host’s cells and use the host’s machinery. To kill the virus, it is often necessary to kill or damage the host cell.
• Key Definitions and Concepts:
  • Spectrum of Activity ($SoA$): Refers to the range of different types of microbes a specific chemotherapy is effective against.
  • Broad-spectrum Antibiotics: Drugs that are effective against a wide range of both Gram-positive ($G+$) and Gram-negative ($G-$) bacteria.
  • Superinfection: Occurs when antibiotics destroy normal microbiota that host the body, allowing resistant or "strong" pathogens to survive and overgrow. These survivors are often made stronger by their exposure to the drug.
  • Bacteriostatic vs. Bactericidal: Bacteriostatic agents stop or slow growth (e.g., Tetracycline), while bactericidal agents kill the bacteria (e.g., Penicillin).

Major Action Modes of Antibacterial Drugs

Antimicrobial drugs target specific essential functions of the microbe to ensure they do not interfere with essential functions of the host. There are five primary modes of action:

1. Inhibition of Cell Wall Synthesis (ICW):
   • Prevents the formation of the bacterial cell wall (e.g., Penicillins, Cephalosporins, Bacitracin, Vancomycin).
2. Inhibition of Protein Synthesis (IPSyn):
   • Targets the bacterial $70\text{s}$ ribosome (composed of $50\text{s}$ and $30\text{s}$ subunits), which is distinct from the mammalian $80\text{s}$ ribosome.
3. Injury to Plasma Membrane (IPMem):
   • Disrupts the integrity of the bacterial plasma membrane (e.g., Polymyxin B).
4. Inhibition of Nucleic Acid Replication and Transcription (INAS):
   • Interferes with DNA replication or RNA synthesis (e.g., Quinolones, Rifampin).
5. Inhibition of Essential Metabolite Synthesis (ISEM):
   • Acts as antimetabolites to block enzyme activity (e.g., Sulfanilamide, Trimethoprim).

Specific Antimicrobial Agents and Their Mechanisms

• Cell Wall Synthesis Inhibitors:
  • Penicillin: Attacks Staphylococci, Streptococci, and Spirochetes. Natural Penicillin G requires injection; Penicillin V can be taken orally. Both contain a $\beta\text{-lactam}$ ring.
  • Semisynthetic Penicillins: Developed to be resistant to $\beta\text{-lactamases}$ (or penicillinase), which are enzymes produced by bacteria to break the $\beta\text{-lactam}$ ring.
  • Cephalosporins: Possess a different $\beta\text{-lactam}$ structure than penicillin; some can be used topically.
  • Vancomycin: A glycopeptide drug used as a response to Methicillin-resistant Staphylococcus aureus (MRSA).
  • Antimycobacterial Agents: Isoniazid and Ethambutol work specifically against the mycolic acid found in the cell walls of Mycobacteria (e.g., Tuberculosis or organisms causing leprosy).
• Protein Synthesis Inhibitors:
  • Chloramphenicol: Reacts with the $50\text{s}$ portion of the ribosome, inhibiting the formation of peptide bonds.
  • Tetracyclines: Interfere with the docking of tRNA carrying amino acids to the $30\text{s}$ subunit.
  • Macrolides (e.g., Erythromycin): Block the tunnel of the $50\text{s}$ subunit.
  • Aminoglycosides: Change the shape of the $30\text{s}$ subunit, causing mRNA to be read incorrectly.
• Nucleic Acid Inhibitors:
  • Rifamycins: Inhibit mRNA synthesis.
  • Quinolones: Inhibit DNA gyrase during replication.
• Metabolite Synthesis Inhibitors:
  • Sulfa Drugs: Structurally similar to PABA, they competitively inhibit microbial growth by blocking enzyme pathways.

Antifungal and Antiviral Modes of Action

• Antifungal Drugs:
  • Target sterols in the cell membrane, specifically ergosterol. Human cells use cholesterol, providing a target for selective toxicity.
  • Can also attack fungal cell walls or inhibit nucleic acid and protein synthesis.
• Antiviral Drugs:
  • Entry/Uncoating Inhibitors: Prevent the virus from entering or releasing its genetic material.
  • Genome Integration/Nucleic Acid Synthesis Inhibitors: Inhibit the integration of viral DNA or the replication of the viral genome.
  • Assembly/Exit Inhibitors: Protease inhibitors prevent assembly, and neuraminidase inhibitors (like those for flu) prevent the virus from budding out of the host cell.
  • Acyclovir: Specifically used for viral infections. It remains inactive in uninfected cells. In an infected cell, viral thymidine kinase converts Acyclovir into a false nucleotide, stopping DNA transcription.

Bacterial Resistance and Diagnostics

• Mechanisms of Antibiotic Resistance:
  1. Blocking Entry: Preventing the drug from crossing the membrane.
  2. Inactivation by Enzymes: Such as $\beta\text{-lactamase}$ destroying penicillin.
  3. Alteration of Target Molecule: Changing the structure of the ribosome or enzyme so the drug no longer binds.
  4. Efflux of Antibiotic: Pumping the drug back out of the cell.
• Minimum Inhibitory Concentration (MIC): A diagnostic test to determine the lowest concentration of an antibiotic that prevents visible bacterial growth.
  • Sensitive: No growth occurs at tested concentrations (e.g., Streptomycin).
  • Resistant: Growth occurs even at high concentrations (e.g., Doxycycline against certain strains).
  • Trailing End Point: Often seen with Sulfamethoxazole, where growth is read at an estimated $80\%$ reduction.

Questions & Discussion

• Q: Who coined the term chemotherapy?
  • A: Paul Ehrlich.
• Q: More than half our antibiotics are produced by a certain genus of bacteria. What is it?
  • A: Streptomyces.
• Q: Why is it difficult to target a virus without damaging the host?
  • A: Viruses rely on and live inside host cells; killing the virus often requires killing the host cell it occupies.
• Q: Why are broad-spectrum antibiotics sometimes less useful?
  • A: They kill helpful "home microbiota" along with the pathogen. If pathogens survive, they face no competition and can become superinfectors.
• Q: What cellular function is inhibited by tetracyclines?
  • A: Protein synthesis (IPSyn). They block tRNA docking sites at the $70\text{s}$ ribosome.
• Q: Why do cell wall synthesis inhibitors not affect mammalian cells?
  • A: Mammals do not have cell walls.
• Q: What prompted the development of semisynthetic antibiotics like methicillin?
  • A: Antibiotic resistance caused by $\beta\text{-lactamase}$ or penicillinase.
• Q: What genus of bacteria has mycolic acids in the cell wall?
  • A: Mycobacteria.
• Q: What sterol in the fungal cell membrane is the target for antifungal action?
  • A: Ergosterol.
• Q: Why does Acyclovir not harm uninfected human cells?
  • A: It only becomes active in the presence of viral thymidine kinase, which is different from human thymidine.
• Q: How does tetracycline interfere with penicillin?
  • A: Tetracycline is bacteriostatic (stops growth). Penicillin only kills bacteria that are actively growing. If tetracycline stops growth, penicillin becomes ineffective.