pharmacology and med chem of protein synthesis inhibitors

• quinupristin/dalfopristin (synecid)

  • dalfopristin: a strepogramin A
  • quinupristin: a streptogramin B
  • synergistic combination (synecid): use to treat MRSA
• MOA of quinupristin/dalfopristin (synecid)

  • the drug combination consists of two semi-synthetic stretogamins
  • they are also called pristinamycins
  • the mechanisms is related to that of the macrolides
  • quinupristin binds to the same site on the 50S ribosomal subunit as macrolides where it causes inhibition of polypeptide elongation and the early termination of protein synthesis
• MOA of quinupristin/dalfopristin (synecid) (cont.)

  • dalfopristin binds at a nearby site and synergistically enhances the binding of quinupristin by modulating the conformation of the ribosome
  • dalfopristin also has a direct effect of inhibiting tRNA binding
  • the combinaiton is bactericidal
  • largely inactive against gram negative
• quinupristin/dalfopristin (synecid)

  • resistance to quinupristin:
  • MLSB mechanism involving ribosomal methylases
  • lactonases that hydrolyze quinupristin
  • resistance to dalfopristin:
  • acetyltransferases that inactivate type A streptogramins
  • ATP binding efflux proteins that pump dalfopristin out of the cell
  • resistance to dalfopristin is necessary for resistance against the combinaiton
  • resistance to quinupristin turns the combination from bactericidal to bacteriostatic
  • making it ineffective against certain infections such as endocarditis
• chloramphenicol

  • seldom used in US but widely used in third world countries bc of its effectiveness and low cost
  • chloramphenicol's problem is its toxicity --> aplastic anemia
  • the anemia is usually fatal
  • toxicity is associated w/ reduction of the aromatic nitro group into active metabolites that damage the stem cells in bone marrow
  • the drug is life saving in certain cases of bacterial meningitis
  • reason for use in US
• MOA of chloramphenicol

  • slightly different than that of macrolides
  • it binds to a site of 50S ribosomes identical or closely related to the binding site of clindamycin and macrolides
  • these drusg interfere each other's binding and antibacterial action
  • the binding of chloramphenicol prevents the binding of the amino acid end of tRNA to the A site of inhibits the action of the peptidyl transferase activity of the ribosome
  • premature termination of synthesis occurs and truncated proteins are released
• basis of selective toxicity

  • again, similar to other bacterial protein syntehsis inhibitors, chloramphenicol relies on the topological differences btwn the bacterial ribosome (50S + 30S) and the mammalian (60S + 40S)
  • binding to the mammalian mitochondria ribosome does occur, contributing to toxicities to erythropoietic cells
• linezolid (oxazoidinones)

  • represents a new class of totally synthetic antimicrobial agents
  • effective only against gram positive organisms
  • MOA
  • bonds to the 50S ribosome subunit and inhibits its formation of the initiation complex w/ the 30S subunit, mRNA, initiation factors and formylmethionyl-tRNA
  • linezolid is bacteriostatic
  • selective toxicity:
  • does not bind to the mammalian 60S ribosome subunits
  • mechanism of resistance:
  • point mutations leading to altered rRNA and decreased binding of the drug to the target