Antibiotics

Antibiotics Overview

• Antibiotics are substances used to kill or inhibit the growth of microorganisms, particularly bacteria.

Therapeutic Index (TI)

• The therapeutic index is an important measurement to assess the safety of antibiotics.

• Equation: TI = (Lowest dose toxic to humans) / (Dose used to kill microorganisms)

• High TI indicates a safe antibiotic, while low TI indicates risk for toxicity to humans.

  • For instance, if it takes 100 gallons to be toxic and only 1 microliter to kill bacteria, the TI is very high, indicating safety.

• Conversely, a low TI may suggest that the drug can only be used topically due to potential harm.

Types of Antibiotics

• Bacteriostatic

  • These antibiotics slow down or inhibit the growth of bacteria, allowing the immune system to combat the pathogens.

• Bactericidal

  • These antibiotics kill the bacteria outright.

• Broad Spectrum vs. Narrow Spectrum

  • Broad Spectrum antibiotics target a wide range of bacteria and are often prescribed initially when the specific pathogen is unknown.

  • Narrow Spectrum antibiotics are used once the specific bacteria is identified, to minimize the impact on beneficial bacteria.

Drug Interactions

• Synergistic Effects

  • When two drugs work together to enhance each other's effectiveness.

• Antagonistic Effects

  • When one drug interferes with the action of another, nullifying any effect.

• Additive Effects

  • The effect of one drug does not interfere with the other.

• Patients may take multiple drugs, necessitating careful consideration by healthcare providers to avoid adverse interactions.

Targeting Unique Aspects of Bacteria

• To effectively attack bacteria, the antibiotic must target something that is unique to them:

  • Cell Wall Synthesis

  • Antibiotics can target peptidoglycan layers unique to bacteria.

  • Example:

    • Bacitracin (low TI) inhibits the transport of peptidoglycan precursors across the membrane, affecting cell wall synthesis.

    • Vancomycin (high TI) binds to the peptide chains in peptidoglycan, blocking cross-linking and effectively killing gram-positive bacteria.

    • Beta-lactam antibiotics (like penicillin) inhibit enzymes (penicillin-binding proteins) involved in cross-linking.

Cell Wall Synthesis Mechanisms

• Bacitracin:

  • Affects transportation of peptidoglycan precursors, hence has a low TI (toxic to human cells).

• Vancomycin:

  • Binds to peptide side chains, preventing cross-linking in gram-positive bacteria.

• Beta-lactam Drugs:

  • Competitive inhibitors of penicillin-binding proteins; crucial for cross-linking in peptidoglycan formation.

  • Characterized by a beta-lactam ring structure.

Understanding Bacterial Resistance

• Resistance Mechanisms

  • Some bacteria produce enzymes that break down antibiotics (e.g., beta-lactamase).

  • Proteins can mutate or change shape, evading the antibiotic's action.

  • Bacteria may enhance their membrane’s selectivity to exclude antibiotics or pump them out post-entry.

• Bacterial resistance is a natural process that increases in visibility with antibiotic use. Overuse does not create resistance; rather, it selects for existing resistant strains.

Strategies Against Protein Synthesis in Bacteria

• Aminoglycosides

  • Kill bacteria by binding to the 30S ribosomal subunit, distorting its shape and preventing correct mRNA reading (streptomycin, neomycin).

• Tetracyclines

  • Block the A-site on the ribosome, preventing tRNA attachment.

• Macrolides (e.g., erythromycin)

  • Bind to the 50S ribosomal subunit, inhibiting translocation along mRNA.

• Chloramphenicol

  • Prevents peptide bond formation between amino acids, affecting protein synthesis.

Inhibitors of Nucleic Acid Synthesis

• Fluoroquinolones

  • Target topoisomerases, enzymes crucial for DNA replication.

• Rifamycins

  • Inhibit RNA polymerase, disrupting RNA synthesis.

Metabolic Pathway Disruption

• Sulfa Drugs

  • Target bacterial metabolism via competitive inhibition of para-aminobenzoic acid (PABA) synthesis into folic acid, which bacteria require but humans cannot synthesize.

concerns about Fungal Infections

• Antifungal drugs have a low TI because fungi are eukaryotic organisms, similar to humans. They often also target cholesterol or ergosterol, leading to potential side effects in humans.

  • **Common Antifungal Classes: **

  • Polyenes: Bind ergosterol in fungal membranes, leading to cell lysis.

  • Azoles: Inhibit ergosterol synthesis, affecting cell membrane permeability.

  • Echinocandins: Weaken fungal cell walls composed of chitin.

Novel Treatments Against Antibiotic Resistance

• Fecal Transplants for C. difficile infections leverage healthy microbiota to outcompete harmful bacteria without using antibiotics.

• Bacteriophage Therapy uses viruses that specifically infect and kill bacteria, providing an alternative approach to antibiotic treatment.

Viruses and Their Treatment

• Effective treatments are made to target viral-specific processes, including:

  • Preventing Uncoating: Drugs that block the release of viral nucleic acids (pleconaril, etc.).

  • Nucleic Acid Synthesis Inhibitors: Using fake bases (e.g., AZT, acyclovir) to create mutations that kill the virus due to lack of proofreading ability in viral polymerases.

  • Protease Inhibitors: Prevents viral proteases from activating viral proteins necessary for replication.

  • Release Inhibition: (Tanaflu) blocks neuraminidase, necessary for virus budding from host cells.

Conclusion

• Ongoing challenges in treating resistant bacterial infections highlight the importance of antibiotic stewardship, research into alternative therapies (bacteriophage therapy), and understanding the mechanisms of resistance. The landscape of antivirals and antifungals also points to the necessity for targeted treatments, particularly as resistance increases.

• Upcoming topics will dive into specific diseases caused by bacteria and viruses, their mechanisms of pathogenesis, and integrated responses to combat them.