polypeptide and lipopeptide antibiotics

• structure features of the polypeptide drugs

  • their molecular weight is relatively high (> 1000)
  • most of them are cyclic
  • they contains D-amino acids or amino acids uncommon in eukaryotic cells (not included in the 20 L-amino acids)
  • they contain non-amino acids moieties, such as glycosides (vancomycin and teicoplanin), lipids (daptomycin), heterocycles (bacitracin)
• mechanism of action of vancomycin and teicoplanin

  • inhibition of transpeptidase in cell wall synthesis by binding to D-Ala-D-Ala glycopeptide terminus
• basis of selectivity of vancomycin and teicoplanin

  • the D-Ala-D-Ala peptide sequence is not commonly seen in eukaryotic cells
  • both compounds are large polar molecules that cannot pass through porin or lipid membranes
  • therefore, they are only active against gram positive bacteria
  • because they are large, polar peptides, they are not absorbed well orally and must be given by parenteral administration (IV for vancomycin and IV/IM for teicoplanin) except for GI tract infections
• mechanism of vancomycin resistance:

  • a plasmid transfer occurs that codes for an enzyme that substitute D-Ala w/ D-lactic acid in the glycopeptide of the cell wall
  • vancomycin binds poorly to the mutated -D-Ala-D-Lactate group and the crosslinking is resumed
• bacitracin

  • separated from a bacteria strain of Bacillus subtilis that was found in the damaged tissue of a young girl named Margaret Treacy in 1943, hend the name
  • structure quite different from vancomycin and teicoplanin, so is the mechanism of action

  
• mechanism of action of bacitracin

  • bacitracin is a high molecular weight compound containing a cyclic peptide component
  • it binds to the pyrophosphate groups of C55-isoprenyl pyrophosphate necessary for the shuttling of glycopeptidyl units to the growing bacterial wall structure
• mechanism of action of bacitracin (cont.)

  • the binding requires a divalent metal ion (predominantly Mg2+, but also Zn2+, Mn2+, and Cd2+) as a bridge btwn bacitracin and pyrophosphate group
  • the bacitracin-metal complex has high affinity to pyrophosphate groups
  • binding of bacitracin to the pyrophosphate groups inhibits the recycling of C55-isoprenyl phosphate, thus inhibiting the cell wall synthesis
• basis of selective toxicity of bacitrin

  • the selectivity is not as solid as most of the antibiotics because the pyrophosphate group is involved in many biochemical pathways in eukaryotic cells
  • when given parenterally, the large, polar compound has high nephrotoxicity
  • it is primarily for topical (ophthalmic and dermatologic) uses
  • limited success was reported for treating GI tract infections
• daptomycin

  • one of the newest antibiotics
  • a lipopeptide
  • active against most strains of gram positive bacteria but inactive against gram negative strains
  • daptomycin is highly bactericidal
• MOA of daptomycin - hypothetical steps

  • step 1: calcium-dependent binding to the cytoplasmic membrane
  • step 2: oligomerization into pores that disrupt the cytoplasmic membrane
  • step 3:
  • disruption of ion gradients
  • membrane depolarization
  • rapid cell death
• mechanism of selectivity of daptomycin

  • the interaction btwn daptomycin and the bacterial membrane also needs a bacterial chaperon protein
  • daptomycin does not interact w/ mammalian cell membranes, which lack the chaperon protein
• resistance to daptomycin

  • the reported resistant strains lacked a chaperon protein which mediates the binding of daptomycin to bacteria cell membrane
  • cross resistance w/ other antimicrobial agents is not likely to occur d/t its unique mechanisms of action