Antimicrobial Chemotherapy

Question 1

What are antimicrobial drugs and examples

Answer 1

• Antimicrobial drugs: Synthetic substances that interfere with growth of microbes, target certain essential functions of microbe
• Inhibiting cell wall synthesis, protein synthesis, nucleic acid synthesis and injuring the plasma membrane or inhibiting synthesis of essential metabolites
• Antimicrobial drug must not interfere with essential functions of the microbes host (toxicity)
• Narrow spectrum: Affect narrow range of microbial types
• Broad-spectrum: Affect gram-positive / negative bacteria

Question 2

What are antibiotics / their susceptibility

Answer 2

• Antibiotics: Naturally produced chemicals / antimicrobial agents, produced naturally by bacteria and fungi that act against other microorganisms
• Less than 1% of known antibiotics are clinically useful, modified to enhance efficacy (semisynthetic)
• Due to toxicity which can affect cell membrane structure, protein synthesis and DNA / RNA synthesis
• Susceptibility: Of microbes to different antibiotics varies greatly, gram-positive / negative vary in sensitivity to antibiotics, broad-spectrum antibiotics are effective against both groups

Question 3

What are the two actions of antimicrobial drugs

Answer 3

• Bactericidal: Actively kills microbes directly, specificity
• Bacteriostatic: Prevents / inhibits microbes from growing (keeps bacteria in stationary phase of growth)

Question 4

Provide an overview of antibiotics that alter cell wall

Answer 4

B lactams 
- penicillin
- cephalosporin
Glycopeptides
- vancomycin
Bacitracin 
Teixobactin

Question 5

Provide an overview of antibiotics that alter plasma membrane

Answer 5

Polymyxin 
- polymyxin B
- polymyxin E (colistin)
Lipopeptide
- daptomycin

Question 6

Provide an overview of antibiotics that alter ribosomes

Answer 6

30s subunit
- aminoglycosides
- tetracyclines
50s subunit
- macrolides
- chloramphenicol
- oxazolidinones

Question 7

Provide an overview of antibiotics that alter DNA / RNA synthesis

Answer 7

Fluoroquinolones (DNA)
- ciprofloxacin
- levofloxacin
- moxifloxacin
Rifamycin (RNA)
- rifampin

Question 8

Provide an overview of antibiotics that alter metabolic pathways

Answer 8

Folic acid synthesis
- sulfonamides
- sulfones
- trimethroprim
Mycolic acid synthesis
- isoniazid

Question 9

Explain effect of penicillins (cell wall)

Answer 9

• Flemming, effective against gram positive bacteria
• Contain B lactam ring (nucleus), natural and semisynthetic
• Prevent cross linking of peptidoglycan, weakened cell walls give rise to lysis
• Penicillin not found in human cells, little toxicity to host
• Penicillinase produced by bacteria attack B lactam ring to inactivate antibiotic

Question 10

Explain effect of semisynthetic penicillins (cell wall)

Answer 10

• Penicillin + B lactamase inhibitors, broad spectrum
• Clavulanic acid
• Carbapenems (substitute C for S atom, add double bond, very broad spectrum)
• Monobactams (single ring only, affects gram negative)

Question 11

Explain effect of B lactams and lysozyme (cell wall)

Answer 11

• B lactams usually decrease cell synthesis in hypotonic (hydrolysis / death) or osmoprotective conditions (oxidative damage / death)
• When lysozyme is present in osmoprotective conditions mutants emerge with increased resistance to oxidative damage
• Increase cell wall digestion by lysozyme
• Conversion of bacteria from rods into spherical ‘L forms’ lack cell walls, B lactam resistant

Question 12

Explain effect of cephalosporins (cell wall)

Answer 12

• The nuclei of cephalosporins resembles that of penicillin, resistant to the action of penicillinases
• Inhibit cell wall synthesis via the same mechanism (prevent cross linking of peptidoglycan)
• Effective against gram negative bacteria
• Resistant to action of penicillinase but sensitive to other B lactamase enzymes

Question 13

Explain effect of bacitracin (cell wall)

Answer 13

• Topical application, derived from B subtilis, effective against gram positive (staph / strep)
• Inhibits cell wall synthesis at an earlier stage than penicillins & cephalosporins
• Interferes with the linear strand of peptidoglycan synthesis, bactericidal
• Blocks activity of peptidoglycan precursors from cytoplasm to exterior of cell
• Nephrotoxic

Question 14

Explain effect of teixobactin (cell wall)

Answer 14

• Inhibits cell wall synthesis by binding to a conserved motif of lipid II (a precursor of PG) and lipid III (a precursor of cell wall teichoic acid), most effective against gram positive
• No mutants with resistance

Question 15

Explain effect of vancomycin (cell wall)

Answer 15

• Glycopeptide
• Inhibits PG / cell wall synthesis by binding directly to D-Ala- D-Ala end of the peptide, forms a cap over the end of the chain, blocks cross-linking, stops bacterial cell wall maturation
• Last line against antibiotic resistant MRSA, limited range of activity

Question 16

What is the central dogma

Answer 16

• Protein Synthesis: DNA - mRNA synthesis - mRNA translation - protein synthesis
• Ribosome: Site of protein synthesis, 30S and 50S subunit portions of 70S prokaryotic ribosomes

Question 17

Explain effect of antibiotics that effect 30s small subunit (protein synthesis)

Answer 17

Aminoglycosides
- Impair proofreading, resulting in production of faulty proteins
- Large, polar, faulty proteins are inserted into cytoplasmic membrane, kills bacterial cells
- Streptomycin
- Nephrotoxic, neurotoxic, ototoxic
Tetracyclines
- Block binding of tRNA, inhibiting protein synthesis
- Treat UTI, mycoplasmal pneumonia, chlamydia
- Phototoxicity, nephrotoxic

Question 18

Explain effect of antibiotics that effect 50s large subunit (protein synthesis)

Answer 18

• Prevent peptide bond formation and stop protein synthesis
  Macrolides (erythromycin)
• Broad spectrum, bacteriostatic block elongation of proteins, inhibit peptide bond between AA
  Chloramphenicol
• Broad spectrum, potentially toxic (suppress bone marrow activity)
• Treat meningitis, typhoid, conjunctivitis
  Oxazolidinones
• New class, response to vancomycin resistance
• Bind to interface between 50s and 30s prevents 70s

Question 19

Explain effect of polymyxins (plasma membrane)

Answer 19

• Change permeability
• Polymyxin B and E
• Lipophilic, interact with lipopolysaccharide portion of outer membrane of gram negative, kills cells
• Narrow spectrum
• Also nephrotoxic / neurotoxic, hence polymyxin B = topical

Question 20

Explain effects of fluoroquinolones (DNA)

Answer 20

• Target DNA replication
• Inhibit activity of DNA gyrase, broad spectrum
• Phototoxicity, neurotoxicity, cardiotoxicity, glucose metabolism dysfunction, increase risk of tendon rupture

Question 21

Explain effects of rifamycin (RNA)

Answer 21

• Target RNA transcription
• Semisynthetic, blocks RNA polymerase activity in bacteria
• Induces hepatotoxicity
• RNA polymerases are structurally difference to humans, selective toxicity

Question 22

Explain effects of sunfonamide / isoniazoid (metabolic pathways)

Answer 22

• Antimetabolites, act as competitive inhibitors for bacterial metabolic enzymes
• Sulfonamides / trimethoprim are antimetabolites that interfere with bacterial folic acid synthesis
• Isoniazid is an antimetabolite that interferes with mycolic acid synthesis in mycobacteria.

Question 23

What are combination drugs

Answer 23

• Synergism: The effect of two drugs together is greater than the effect of either alone, key-hole formation
• Antagonism: The effect of two drugs together is less than the effect of either alone, D growth, growth of bacteria resistant to drug D, truncation effect of zone of inhibition