antimicrobial targets

• what is selective toxicity?

  which is the ability of a drug to suppress (bacteriostatic -stop it from growing) or kill (bactericidal) an infecting microbe without injury to the host
• why is selective toxicity achievable?

  because the drug accumulates in a microbe at a higher level than in human cells + the drug has a specific action on cellular structures or biochemical processes that are unique to the microbe or more harmful to the microbe
• what can drugs specially target in bacteria?

  • cell wall synthesis
  • protein synthesis
  • nucleic acid synthesis
  • cell membrane functioning
  • essential metabolite production
• what is the target for inhibiting cell wall synthesis in bacteria?

  • targets peptidoglycan synthesis e.g. penicillins, cephalosporins
  • unique to bacteria - no other organism has peptidoglycan
• how do drugs target protein synthesis in bacteria?

  Targets 30S and 50S ribosomes e.g. tetracyclines, chloramphenicol
• what do drugs target for inhibition of nucleic acid synthesis?

  • targets the supercoiling of DNA via inhibiting enzymes like DNA gyrase e.g. quinolone such as ciprofloxacin
• cell membrane functioning target - causes membrane disruption
• essential metabolite production target - targets folic acid production e.g. trimethoprim
• whats the morphology of bacterial peptidoglycan?

  NAM = N-acetlymuramic acid

  NAG = N-acetylglucosamine

  Both are sugar derivatives and linked together by glycosidic bonds

  A) Diaminopimelic acid

  
• what are the potential targets in peptidoglycan?

  D-Alanine, N-acetylglucosamine (NAG), N-acetylmuramic acid (NAM)
• describe the synthesis of cell wall of bacteria?

  1. A loss of a terminal D-alanine residue (pentopeptide reduce down to a tetra peptide). This allows space for a newly synthesised peptidoglycan to join - this is brought about by a transpeptidase reaction
  2. Interbridge links new synthesised and pre-existing peptidoglycan (pentaglycine the most common/most simplest form interbridge made of 5 glycine residues)

  
• how do beta-lactam antibiotics inhibit cell wall synthesis?

  They inhibit enzymes called transpeptidases (they're penicillin-binding proteins) which are responsible for cross-linking the peptidoglycan chains in the bacterial cell wall. They prevent the loss of the D-alanine residue so the new peptidoglycan has no space to join (tetraglycan not formed) and so peptidoglycan becomes thin and so weak = initiates osmotic shock
• what other type of antibiotics inhibit cell wall synthesis in bacteria?

  Glycopeptide - e.g. Vancomycin and Bacitracin
• how does Vancomycin inhibit cell synthesis?

  It binds to precursors of peptidoglycan, preventing their incorporation into the growing cell wall - particularly effective again gram-positive bacteria - blocks the reaction site (binding site) for the transpeptidase to act
• how does Bacitracin inhibit cell wall synthesis?

  The newly formed NAM and NAG are synthesised within the cell and has to be exported through the cell membrane - Bacitracin blocks the passage for the building block (NAM) for peptidoglycan through the membrane.
• what are the subunits for eukaryote ribosomes?

  40S and 60S
• why can bacterial ribosomes be subjected to selective toxicity?

  ribosomes in prokaryotic on a smaller scale than eukaryotic
• what drugs can inhibit protein synethsis?

  A) Aminoglycosides

  B) Chloramphenicol

  C) Erythromycin

  D) Tetracycline

  
• how does aminoglycosides inhibit protein synthesis?

  binds to 30S subunit causing the misreading of the genetic code during translation (inhibits proof reading and initiation) - incorrect amino acids on polypeptide = nonfunctional or toxic proteins
• how does tetracyclines inhibit protein synthesis?

  bind to 30S and blocks the binding of aminoacyl-tRNA to the A site of ribosome, preventing the addition of new amino acids
• how do erythromycin inhibit protein synthesis?

  binds to 50S and inhibits translocation, by preventing the movement of the ribosome along the mRNA it interferes with the elongation of the polypeptide chain
• how does chloramphenicol inhibit protein synthesis?

  binds to 50S subunit inhibiting transpeptidation by inhibiting the peptidyl transferase activity. Blocks the formation of peptide bonds between the amino acids
• whats the composition of bacterial chromosome?

  • double stranded DNA
  • 1 type of chromosome per cell
• what is the function of bacterial chromosome?

  • essential - keep it alive
  • housekeeping genes - optimise growth and survival in whatever environment it finds itself in
• whats the morphology of a bacteria chromosome?

  • circular, covalently closed
  • 1-2mm long
  • supercoiled domains

  
• how do Quinolones and Fluoroquinolones inhibit nucleic acid synthesis?

  Q - inhibit DNA gyrase (enzyme involved in the winding and unwinding of DNA during replication and transcription) - it leads to the accumulation of DNA breaks

  F - a more advanced class of Q . inhibits both DNA gyrase and topoisomerase IV (enzyme involved in DNA processing) - this dual inhibition further disrupts DNA replication + transcription
• how do Rifamycins inhibit nucleic acid synthesis?

  inhibits RNA polymerase (responsible for transcribing DNA into RNA during transcription) by binding to the beta subunit of RNA polymerase preventing RNA synthesis
• what do plasmids do?

  Plasmids are small, circular DNA molecules that can replicate independently within a cell. They often carry genes that provide advantages to the host cell, such as antibiotic resistance or the ability to produce certain proteins.
• whats the morphology of plasmids?

  • circular
  • extrachromosomal
  • number & distribution variable
• whats the composition of plasmids?

  double stranded DNA
• whats the function of plasmids?

  bring about specialised functions to micro-organisms e.g antibiotic resistance, fertility 
• how is energy metabolism a target area?

  In gram-negative cell membrane - can disrupt the outer membrane and get through there to disrupt the cell wall

  
• essential metabolite as a target:

  PABA needs to get in to cell to be converted into folic acid - sulphonamides prevents the entry

  A) dihydrofolic acid

  B) tetrahydrofolic acid

  C) Trimethoprim

  
• why do fungi pose special problems for chemotherapy?

  because they are eukaryotic - biochemical - much of the cellular machinery is the same as that of animals and humans

  • as a result, many anti-fungals are tropical
  • a few drugs target unique metabolic processes unique to fungi
• what are the anti-fungal targets?

  • cell wall synthesis
  • membrane functions
  • ergosterol synthesis
  • nucleic acid synthesis
  • microtubule formation
• anti-fungal - cell wall synthesis:

  • polyoxins inhibits chitin synthesis - not all fungal species have chitin
  • echinocandins inhibits glucan synthesis
• anti-fungal - membrane functions...?

  polyenes binds to ergosterol and disrupt membrane integrity/fluidity of the cell membrane - ergosterol efficient to act as a selective target (this is the main target in fungal cells)
• anti-fungal - ergosterol synthesis?

  azoles and allylamines inhibit synthesis
• nucleic acid synthesis - anti-fungal?

  5-Fluorocytosine is a nucleotide analog that inhibits nucleic acid synthesis 
• microtubule formation - anti-fungal target?

  Griseotulvin disrupts microtubules aggregation during mitosis