tetracyclines

• MOA of tetracyclines

  • tetracyclines enter bacterial cells by active transport across the plasma membrane (inner membrane for gram negatives)
  • tetracyclines, as their Mg2+ complex, bind to a specific site at the aminoacyl-tRNA binding site on the 30S ribosome unit
  • binding of aminoacyl-tRNA units is inhibited and protein synthesis is suppressed
  • the binding site is different than that for the aminoglycosides or other antimicrobial agents that inhibit protein synthesis
• MOA of tetracyclines (cont.)

  • tetracyclines are usually bacteriostatic rather than bactericidal
  • unlike aminoglycosides, the tetracyclines do not allow the syntehsis of non-functional or partly functional proteins
  • also, most tetracyclines do not bind the ribosomes as tightly as aminoglycosides
  • tetracycline/Ca2+ complexes deposit in teeth and bones
• selective toxicity of tetracyclines

  • selective accumulation of tetracyclines by bacteria
  • concentrations inside bacterial cells will reach 30 times the external concentration
  • mammalian cells do not actively import tetracyclines
  • some tetracyclines does get into mammalian cells by diffusion; however, concentrations aren't as high and tetracyclines do not bind as tightly to 40S ribosomal units
  • mammalian mitochondrial ribosomes are inhibited only at over-dosage of tetracyclines
• major mechanism of tetracycline resistance

  • loss of accumulation
  • mutations in the uptake pumps that accumulate tetracyclines (eg, OmpF) and the induction of efflux pumps (Tet efflux proteins, eg: TetA, TetK) both occur
  • cross resistance in the class is common but not absolute
  • induction of ribosome protection proteins
  • these proteins bind to the 30S subunit in such a manner that blocks tetracycline binding but not the binding of aminoacyl-tRNA
  • translation is thus restored
  • cross resistance to all tetracyclines occurs
• spectrum of activity of tetracyclines

  • broadest spectrum of activity but are less potent
  • usage limited by drug resistance
  • penicillins preferred for serious infections by gram positive bacteria
• recent develpoment

  • tigecycline, a glycine derived new tetracycline is more potent in vitro and has been developed for treating infections caused by bacteria strains that are resistant to commonly used tetracyclines (tetracycline, minocycline, doxycycline), methicillin or vancomycin