ANTIBACTERIAL AGENTS: BETA-LACTAM

• What is the structure of Gram-positive bacteria?

  Thick cell wall surrounding the membrane

  
• What is the structure of Gram-negative bacteria?

  Thin cell wall covered by a complex outer membrane

  
• What are the mechanisms of action for antimicrobials?

  • Inhibition of cell metabolism
  • Inhibition of cell wall synthesis
  • Interaction with the plasma membrane
  • Disruption of protein synthesis
  • Inhibition of nucleic acid transcription and replication
  • Miscellaneous mechanisms

  
• What is an example of an antimicrobial that inhibits cell metabolism?

  Sulphonamides
• What is the first synthetic antibacterial agent active against a wide range of infections?

  Sulphanilamide
• What is the significance of the para-amino group in sulphonamides?


  It is essential for activity and must be unsubstituted
• What are the problems associated with sulphonamides?

  They are ineffective against Salmonella and yield toxic metabolites
• What is a fatal consequence of sulphonamide toxicity?

  Blocking kidney tubules
• What is the role of trimethoprim in combination with sulphonamides?

  It inhibits dihydrofolate reductase to stop DNA synthesis

  
• Who discovered penicillin and when?

  Fleming in 1928
• What did Fleming observe when he returned from vacation?

  Bacteria surrounding mold were dead
• What was the problem solved in 1938 regarding penicillin?

  Isolating penicillin using freeze-drying and chromatography
• What technique was used to establish the structure of penicillin?

  X-ray crystallography

  
• What was the yield of the 5-step synthesis of penicillin shown by Sheehan in 1957?

  1% yield
• What is the significance of 6-aminopenicillanic acid (6-APA)?

  It opened the door to semi-synthetic penicillins

  
• What determines the acyl chain (R) in penicillins G and V?

  Fermentation medium

  
• What is the theoretical method for synthesizing different acyl side chains in penicillins?

  Addition of different carboxylic acids to fermentation medium
• What is the modern method for producing 6-APA?

  Hydrolysis of penicillin G

  
• What is the enzyme responsible for the cross-linking reaction in cell wall synthesis?

  Transpeptidase

  
• Why is penicillin thought to work effectively?

  Its conformation resembles the transition state of D-Ala-D-Ala

  
• What is a reason for varying susceptibility to penicillins among bacterial strains?

  Presence of β-lactamases
• What is a physical barrier that prevents penicillin from reaching the bacterial cell membrane?

  The bacterial cell wall

  
• What role do porins play in Gram-negative bacteria?

  They provide a transport route for drugs

  
• What is the most important mechanism for bacteria to gain resistance to penicillin?

  Production of β-lactamase enzymes
• How do Gram-positive bacteria release β-lactamase?

  Into the surrounding environment
• Why aren't all Gram-negative bacteria resistant to penicillin?

  Some produce β-lactamases trapped in periplasmic space
• What is the significance of the different types of β-lactamase enzymes?

  They have varying selectivity for penicillins and cephalosporins
• What happens when Gram-negative bacteria produce large amounts of transpeptidase?

  Penicillin cannot inhibit all the enzyme present

  
• What is the issue with S. aureus strains regarding transpeptidase?

  They acquired PBP2a with low affinity for penicillin
• What is the role of efflux pumps in Gram-negative bacteria?

  They pump penicillins out of the periplasmic space

  
• What are some issues with penicillins besides resistance?

  Sensitivity to acids and limited breadth of activity
• How can the structure of penicillins be changed to improve their properties?

  By adding electron withdrawing groups
• What is the only solution to tackle acid sensitivity in penicillins?

  Reduce neighboring group participation
• What is the purpose of isoxazoyl penicillins?

  To tackle both acid and β-lactamase sensitivity
• What factors determine the spectrum of activity for penicillins?

  • Structure
  • Ability to cross cell membrane
  • β-lactamase susceptibility
  • Affinity for target enzyme
  • Rate of efflux

  
• What happens when hydrophobic groups are added to the side chain of penicillins?

  Gram-positive activity increases, Gram-negative decreases
• What is the effect of adding hydrophilic groups to the side chain of penicillins?

  Gram-negative activity increases, Gram-positive decreases
• What are aminopenicillins known for?

  Being common first line of defense
• What is a characteristic of carboxypenicillins?

  They are broad-spectrum penicillins
• What is unique about ureidopenicillins?

  They are the newest class of broad-spectrum penicillins