🌍 Lesson 2 – Antimicrobial Drugs, Resistance & Strategies

💊 Antimicrobial Drugs

• Definition: Kill or inhibit microbes inside the host.
• Goal: Selective toxicity → attack microbes, not host cells.
• Types:
  • Natural antibiotics: produced by bacteria/fungi.
  • Synthetic drugs: man-made versions or modifications.
• Spectrum:
  • Narrow-spectrum (e.g., penicillin G) → mainly gram-positives.
  • Broad-spectrum (e.g., tetracycline) → work on both gram-positive & gram-negative.
• Key Targets: cell wall 🧱, ribosomes 🎶, nucleic acid enzymes 📖, cytoplasmic membrane 🧬.

🧱 Cell Wall Targeting Drugs

• β-lactams (penicillins, cephalosporins):
  • Share the β-lactam ring structure.
  • Inhibit transpeptidation → no cross-linking of peptidoglycan → bacteria burst.
• Penicillin G: only works on gram-positives, destroyed by β-lactamases.
• Semisynthetic penicillins (ampicillin, carbenicillin, methicillin, oxacillin): modified to broaden activity or resist β-lactamases.
• Cephalosporins: similar action but more resistant to β-lactamases; ceftriaxone is key for gonorrhea.
• Vancomycin: narrow-spectrum, last resort for resistant gram-positives.

🧬 Growth Factor Analogs

• Mimic essential nutrients but sabotage metabolism.
• Isoniazid: analog of nicotinamide, blocks mycolic acid synthesis → effective vs. Mycobacterium tuberculosis.
• Sulfa drugs (sulfonamides): mimic PABA, block folic acid synthesis.
• Often combined with trimethoprim for double blockade → harder for bacteria to resist.

🎶 Protein Synthesis Inhibitors (ribosome attackers)

• Aminoglycosides (streptomycin, gentamicin, kanamycin): target 30S; toxic (kidney/ear damage).
• Tetracyclines: 30S inhibitors, broad-spectrum, but stain teeth and weaken bones (🚫 for kids/pregnant women).
• Macrolides (erythromycin, azithromycin, clarithromycin): 50S inhibitors; useful alternative for penicillin allergies.
• Chloramphenicol: powerful but risky (bone marrow toxicity).

📖 Nucleic Acid Synthesis Inhibitors

• Quinolones (nalidixic acid, ciprofloxacin, moxifloxacin): block DNA gyrase → prevent DNA supercoiling.
  • Ciprofloxacin: treats anthrax.
  • Moxifloxacin: effective against TB.
• Rifamycins (rifampin): block RNA polymerase; used for TB, but makes sweat/urine/tears turn orange-red 🧡.
• Actinomycin: binds DNA and blocks transcription elongation.

🧪 Other Drug Targets

• Daptomycin: lipopeptide that makes pores in membranes → depolarization → cell death.
• Platensimycin: blocks fatty acid synthesis, effective vs MRSA & VRE, no host toxicity 🚀.

🦠 Antimicrobial Resistance (AMR)

• Definition: Microbes gain ability to resist drugs they were once sensitive to.
• Genetic Basis: Often carried on R plasmids → spread via horizontal gene transfer.
• Mechanisms:
  1. Drug inactivation (enzymes like β-lactamases).
  2. Altered targets (ribosomes, RNA polymerase, DNA gyrase).
  3. Reduced permeability (block entry).
  4. Efflux pumps (spit drug out).
  5. New biochemical pathways (e.g., bypass folic acid blockade).

📉 Example: Neisseria gonorrhoeae

• 1980s: Penicillin stopped working.
• 1990s–2000s: Ciprofloxacin lost effectiveness.
• Now: ceftriaxone + azithromycin combo used.

🧬 New Strategies Against Resistance

• Drug analogs: tweak existing drugs (e.g., modified penicillins, vancomycin derivatives).
• Computer-designed drugs: e.g., Saquinavir & Indinavir (HIV protease inhibitors).
• Combination therapy:
  • Augmentin = amoxicillin + clavulanic acid (β-lactamase inhibitor).
  • HAART for HIV = nucleoside analog + protease inhibitor.
• Novel targets: e.g., platensimycin disrupting lipid biosynthesis.
• Prudent use: avoid overuse in farming & medicine; patients should finish prescriptions.

✅ Key Review Points

• Selective toxicity = killing microbes without harming host.
• Different classes of antibiotics target walls, ribosomes, nucleic acids, or membranes.
• Resistance mechanisms are diverse and spreading quickly.
• New strategies = analog design, combo therapy, new targets, and cautious antibiotic use.