Topic 9-Antimicrobial Drugs

• Chemotherapy


  The use of drugs to treat a disease
• Antimicrobial drugs


  Interfere with the growth of microbes within a host
• Antibiotic


  A substance produced by a microbe that, in small amounts, inhibits another microbe
• Selective toxicity


  A drug that kills harmful microbes without damaging the host
• Fleming discovered penicillin, produced by Penicillium


  1928
• Howard Florey (Aussie) and Ernst Chain performed first clinical trials of penicillin


  1940
• All 3 (Fleming, Florey, Chain) won a Nobel Prize in 1945
• Penicillin made a huge impact on reducing allied losses during the final year of the second world war
• Previously - war wound = amputation or death by infection
• Paul Ehrlich


  Every cell is different
• Wiradjuri Aboriginal people used Pycnoporus (orange bracket fungi) as a traditional medicine against mouth ulcers and as a teething ring for kids
• Fresh slices of the Pycnoporus fungi were active against Staphylococcus aureus
• The probable antibiotic is cinnabarinic acid
• When it rains, the enzyme laccase produces antibiotics in Pycnoporus
• Microbes producing antibiotics


  • Actinomycetes, filamentous soil bacteria
  • Other soil bacteria
• Actinomycetes are responsible for a large diversity of antibiotics, around 50-60% of them
• The clearing around the Actinomycetes bacteria is due to an antibiotics inhibiting encroachment
• Soil organisms are fighting for space or a niche in Nature, and antibiotics are one of their weapons to claim that niche
• Bactericidal


  Kill microbes directly
• Bacteriostatic


  Prevent microbes from growing
• A bacteriostatic antibiotic would give the immune system time to beat an infection
• Broad spectrum antibiotic


  Protects against many types of microbes
• Narrow spectrum antibiotic


  Targets specific microbe
• Superinfection


  A secondary infection follows an infection, and is resistant to the original antibiotic
• Modes of action of antimicrobial drugs


  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Inhibition of nucleic acid replication and transcription
  • Injury to plasma membrane
  • Inhibition of synthesis of essential metabolites
• Inhibition of cell wall synthesis

  • Penicillin, cephalosporins, bacitracin, vancomycin
• Inhibition of protein synthesis

  • Chloramphenicol, erythromycin, tetracyclines, streptomycin
• Inhibition of nucleic acid replication and transcription

  • Quinolones, rifampin
• Injury to plasma membrane

  • Polymyxin B
• Inhibition of synthesis of essential metabolites


  • Sulphanilamide, trimethoprim
• Natural penicillin


  Fleming's penicillin turned out to be 5 related compounds, including Penicillin G and Penicillin V
• Semisynthetic penicillin


  Natural penicillin is first cleaved by an acylase, then an addition is made at the acyl-group
• Penicillin G has a half-life of about 1 hour, requiring frequent injections
• Oral penicillin G is destroyed by stomach acid
• Addition of procaine to the injection allows a large amount of the antibiotic to be injected, indicated against erysipelas and cellulitis
• Penicillinases (B-lactamases) can break down the B lactam ring, rendering the drug useless
• Some bacteria produce penicillinases, which can be stopped by mixing a penicillinase inhibitor with penicillin, e.g. clavulanic acid
• Inhibitors of cell wall synthesis


  • Penicillin (penicillinase-resistant penicillins, penicillins + beta-lactamase inhibitors)
  • Carbapenems
  • Monobactam
  • Cephalosporins (first-generation, second-generation, third-generation, fourth-generation)
• Cephalosporins


  Have a 6-membered ring, are not susceptible to penicillinases, and have a broader spectrum of activity including gram-positive and gram-negative bacteria
• Polypeptide antibiotics


  • Bacitracin (topical application, against gram-positives)
  • Vancomycin (glycopeptide, important "last line" against antibiotic-resistant S. aureus MRSA)