Treatment of infections: Antibacterial MoA

• 3 AB sources

  1. microorgs = penicillin from penicillium notatum

  2. synthesis = chloramphenicol

  3. semi-synthesis = amoxicillin
• bactericidal meaning?


  kills bacteria
• bacteriostatic meaning?


  slow down or stall bacterial growth
• selective toxicity meaning?


  selectively kills/inhibits target organism whilst causing no or minimal harm to host
• 4 AB sites of action

  1. cell wall = main target, unique to prokaryotes as provides selective target

  2. cell membrane = fewer drugs due to similarity to body cells

  3. protein synthesis = exploit differences between prokaryotic and eukaryotic ribosomes

  4. nucleic acid synthesis = different cellular machinery as bacteria lack nucleus

  
• Which of the 4 sites of action is mainly bacteriostatic?

  protein synthesis
• Gram positive cell wall

  - thick PG layer (techoic and lipotechoic acids)

  - e.g. E.Coli

  
• Gram negative cell wall

  - thin PG layer

  - outer membrane (lipopolysacharrides and porin channels)

  - e.g. streptococcus

  
• Main differences between bacterial cell walls

  - G+ve has no outer membrane or porin channels

  - G+ve has a thicker PG layer

  - G-ve is harder to treat

  
• beta-lactams


  - all contain beta lactam ring

  - differences in structure of ring attached to beta-lactam and R group

  - some can pass through porin channels so some can treat G-ve

  - e.g. penicillin, carbapenem

  
• 3 beta-lactam MoA

  1. direct = bind to and inhibit action of transpeptidases usually known as Penicillin Binding Proteins (PBPs) - prevents x-linking, prevents stable formation of PG leading to cell lysis

  2. direct = get incorporated into peptide side chain causing same effect as above

  3. indirect = stimulate bacteria to produce autolysins - break down cell wall causing cell lysis

  
• what are glycopeptides?

  - bind to terminal AAs on peptide side chain of monomer: 1. prevents x-linking of peptide side chains 2. prevents glycosylase from adding PG monomer onto PG chain

  - only acts on G+ve as too big to enter G-ve membrane

  
• what are lipopeptides and polymyxins?

  - cell membrane antibiotics

  - bind to lipid A, distorts membrane, penetrates cell wall, secondary effect, disrupts membrane integrity - allows leakage of cytoplasmic contents

  - reserved for treating serious G-ve infections
• 4 nucleic acid antibiotic types?

  1. metabolic inhibitors of NA synthesis = sulphonamides, trimethoprim

  2. affect DNA replication = fluoroquinolones

  3. affect RNA polymerase = rifamycins

  4. affect DNA = nitroimidazoles
• What are fluoroquinolones?


  - e.g. Ciprofloxacin, Levofloxacin

  - bind to and inhibit DNA gyrase a/o topoisomerases IV when complexed with bDNA

  - DNA gyrase removes DNA supercoils ahead of replication

  - topoisomerase IV separates DNA after replication

  - inhibits DNA replication and packaging of DNA in cell - bacterial cell lysis

  
• what are bribosomes?


  - 10x faster, 50S and 30S subunit

  
• what are tetracyclines?


  - binds reversibly (bacteriostatic) to A-site on 16S rRNA in 30S subunit

  - inhibits binding of tRNA to A-site thus inhibiting protein synthesis

  - selectivity through better binding to bribosomes and better accumulation of ABs inside bacterial cell

  
• what are aminoglycosides?


  bind irreversibly (bactericidal) to A-site on 16S rRNA in 30S

  
• aminoglycoside 4 modes


  1. prevent formation of initiation complex

  2. inhibit binding of tRNA to A-site

  3. cause misreading of codons (dysfunctional proteins)

  4. increase bacterial membrane permeability