Antibiotics: mechanisms and bacterial resistance (L2)

• Anti-microbial agents


  Naturally occurring or chemically synthesized substances intended to be toxic for the pathogenic organisms but harmless to the host. This include antibiotics, antifungals, antivirals and antiparasitics
• Antibiotic


  A natural substance, or derivative of a natural substance, which when taken in small doses will either kill or prevent the growth of bacteria, but will not seriously harm the person taking it
• Classification of antibiotics


  • Mode of action
  • Chemical structure
  • Spectrum of activity
  • Effect on organism
• Broad spectrum of activity


  Antimicrobial drug effective against large variety of microbes. Disadvantage - high likelihood of destroying friendly bacteria of patient's normal microbial flora
• Narrow spectrum of activity


  Antimicrobial drug that is effective against only a relatively small subset of bacteria
• Bactericidal


  Interaction results in an irreversible disruption or binding → cell death
• Bacteriostatic


  Interaction involves lower affinity binding and is reversible when antibacterial is removed from environment
• Mode of Action


  • Inhibition of cell wall synthesis
  • Disruption of cell membrane function
  • Inhibition of protein synthesis
  • Inhibition of nucleic acid synthesis
  • Inhibition of metabolic pathways
• Synthesis of peptidoglycan cell wall

  1. Bacteria increase their size following binary fission

  2. Bacterial enzymes " autolysins" breaks the glyosidic bonds between the peptidoglycan monomers and the peptide cross-bridages that link the rows sugar together

  3. Insertion of new peptidoglycan monomers to enable bacterial growth

  4. Transglycosidase enzyme catalise the formation of the glycosidic bonds

  5. Transpeptidase enzymes reform the peptide crosslink between the two rows and layers of the peptidoglycan

  
• Penicillins and cephalosporins


  Bind to the transpeptidase enzymes (also knows as penicillin binding protein) which will result in weakening the bacterial cell wall

  
• Penicillin


  Discovered by accident Alexander Fleming in 1928, produced by Penicillium fungi, works by inhibiting the cell wall synthesis through binding and inhibiting transpeptidase enzymes
• Polymyxins, Nystatin, Amphotericin B

  Bind to the lipid membrane of the cell to forms pores in the membrane that lead to ions leakage, acidification, disturbance to the membrane functionality consonantly, microorganism cell death
• Inhibitors of protein synthesis

  • Aminoglycosides
  • Tetracyclines
  • Chloramphenicol, clindamycin
  • Macrolides
• Aminoglycosides


  Irreversibly bind to 16s ribosomal RNA and changes shape of 30s subunit, causing misreading of code on mRNA
• Tetracyclines


  Bind reversibly to 30S ribosome and inhibit binding of t-RNA to acceptor site on the 70S ribosome
• Chloramphenicol, clindamycin


  Binds to 50S ribosome and inhibit peptidyl transferase activity, hence no peptide bonds

  
• Macrolides


  Binds to 50s portion and prevents translocation of ribosome along mRNA
• Rifampicin


  Bind to DNA-dependent RNA polymerase and inhibit initiation of RNA synthesis
• Quinolones - Nalidixic acid, Ciprofloxacin


  Bind to the A subunit of DNA gyrase and prevent supercoiling of DNA (essential for DNA replication)
• Metronidazole


  The nitro group is reduced by the bacteria, and this reduced form of the drug causes strand breaks in DNA
• Inhibition of metabolic pathways

  • Sulphonamides
  • Trimethoprim
• Sulphonamides


  Blocks thymidine & purine synthesis by inhibiting microbial folic acid synthesis
• Trimethoprim


  Bind to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid
• Antimicrobial therapy


  • Empiric
  • Definitive
  • Prophylactic or preventative
• Empiric


  Infecting organism(s) not yet identified, more "broad spectrum"
• Definitive


  Organism(s) identified and specific therapy chosen, more "narrow" spectrum
• Prophylactic or preventative


  Prevent an initial infection or its recurrence after infection
• Drug resistance


  Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth. Microbial species may become resistance through spontaneous mutation or acquired resistance.
• Mechanism of Bacterial Resistance

  • Active pumping out of substrate (efflux pumps)
  • Enzymatic inhibition
  • Membrane impermeability
  • Alteration in target site, e.g. Mutation
  • Alteration in target enzyme
  • Over production of target enzyme
• Anti-microbial agents


  Naturally occurring or chemically synthesized substances intended to be toxic for the pathogenic organisms but harmless to the host. This include antibiotics, antifungals, antivirals and antiparasitics
• Antibiotic


  A natural substance, or derivative of a natural substance, which when taken in small doses will either kill or prevent the growth of bacteria, but will not seriously harm the person taking it
• Classification of antibiotics


  • Mode of action
  • Chemical structure
  • Spectrum of activity
  • Effect on organism
• Broad spectrum of activity


  Antimicrobial drug effective against large variety of microbes. Disadvantage - high likelihood of destroying friendly bacteria of patient's normal microbial flora
• Narrow spectrum of activity

  Antimicrobial drug that is effective against only a relatively small subset of bacteria
• Bactericidal


  Interaction results in an irreversible disruption or binding → cell death
• Bacteriostatic


  Interaction involves lower affinity binding and is reversible when antibacterial is removed from environment
• Mode of Action


  • Inhibition of cell wall synthesis
  • Disruption of cell membrane function
  • Inhibition of protein synthesis
  • Inhibition of nucleic acid synthesis
  • Inhibition of metabolic pathways
• Synthesis of peptidoglycan cell wall

  1. Bacteria increase their size following binary fission

  2. Bacterial enzymes " autolysins" breaks the glyosidic bonds between the peptidoglycan monomers and the peptide cross-bridages that link the rows sugar together

  3. Insertion of the new peptidoglycan monomers which will enable the bacterial growth

  4. Transglycosidase enzyme catalise the formation of the glycosidic bonds between the N-acetyle muramic acid (NAM) and N-acetyl glucosamine (NAG) of the new peptidoglycan monomer with the existing peptidoglycan

  5. Transpeptidase enzymes (also knows as penicillin binding protein) reform the peptide crosslink between the two rows and layers of the peptidoglycan which makes the wall stronger

  
• Penicillins and cephalosporins


  Binds to the transpeptidase enzymes (also knows as penicillin binding protein) which will result in weakening the bacterial cell wall. As such some area of the cell wall will be weak, subsequently burst the cell due to osmotic lysis

  
• Penicillin

  Works by inhibiting the cell wall synthesis through binding and inhibiting transpeptidase enzymes involved in transpeptidation of peptidoglycan