Antimicrobial Chemotherapy Flashcards
What are antimicrobial drugs and examples
- 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
What are antibiotics / their susceptibility
- 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
What are the two actions of antimicrobial drugs
- Bactericidal: Actively kills microbes directly, specificity
- Bacteriostatic: Prevents / inhibits microbes from growing (keeps bacteria in stationary phase of growth)
Provide an overview of antibiotics that alter cell wall
B lactams - penicillin - cephalosporin Glycopeptides - vancomycin Bacitracin Teixobactin
Provide an overview of antibiotics that alter plasma membrane
Polymyxin - polymyxin B - polymyxin E (colistin) Lipopeptide - daptomycin
Provide an overview of antibiotics that alter ribosomes
30s subunit - aminoglycosides - tetracyclines 50s subunit - macrolides - chloramphenicol - oxazolidinones
Provide an overview of antibiotics that alter DNA / RNA synthesis
Fluoroquinolones (DNA) - ciprofloxacin - levofloxacin - moxifloxacin Rifamycin (RNA) - rifampin
Provide an overview of antibiotics that alter metabolic pathways
Folic acid synthesis - sulfonamides - sulfones - trimethroprim Mycolic acid synthesis - isoniazid
Explain effect of penicillins (cell wall)
- 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
Explain effect of semisynthetic penicillins (cell wall)
- 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)
Explain effect of B lactams and lysozyme (cell wall)
- 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
Explain effect of cephalosporins (cell wall)
- 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
Explain effect of bacitracin (cell wall)
- 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
Explain effect of teixobactin (cell wall)
- 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
Explain effect of vancomycin (cell wall)
- 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
What is the central dogma
- Protein Synthesis: DNA - mRNA synthesis - mRNA translation - protein synthesis
- Ribosome: Site of protein synthesis, 30S and 50S subunit portions of 70S prokaryotic ribosomes
Explain effect of antibiotics that effect 30s small subunit (protein synthesis)
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
Explain effect of antibiotics that effect 50s large subunit (protein synthesis)
- 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
Explain effect of polymyxins (plasma membrane)
- 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
Explain effects of fluoroquinolones (DNA)
- Target DNA replication
- Inhibit activity of DNA gyrase, broad spectrum
- Phototoxicity, neurotoxicity, cardiotoxicity, glucose metabolism dysfunction, increase risk of tendon rupture
Explain effects of rifamycin (RNA)
- Target RNA transcription
- Semisynthetic, blocks RNA polymerase activity in bacteria
- Induces hepatotoxicity
- RNA polymerases are structurally difference to humans, selective toxicity
Explain effects of sunfonamide / isoniazoid (metabolic pathways)
- 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.
What are combination drugs
- 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
