macrolides/ketolide

• structural features of macrolide antibiotics

  • 3 drugs of this class are marketed in US:
  • erythromycin
  • clarithromycin
  • azithromycin
  • structural features:
  • 1) a large lactone ring, thus the name macrolide
  • 2) a ketone group tat C9 except in azithromycin
  • 3) a glyco-residue at C3
  • 4) an aminoglyco-reside (so is in aminoglycosides) at C5
• MOA of macrolides

  • macrolides enter bacterial cells by passive diffusion
  • since the drugs contain a basic tert-nitrogen, they penetrate bacterial cells better at high pH (i.e., alkaline tissue)
  • gram positive bacteria accumulate up to 100 times more erythromycin than ram negative organisms
  • more active on aerobic gram positive organisms
  • macrolides bind to the 50S ribosome subunit
  • the binding inhibits translocation of the growing peptide chain from the aminoacyl site (A site) to the adjacent peptidyl binding site (P site) along the ribosome
  • thus protein synthesis is inhibited
• MOA of the macrolides (cont.)

  • macrolides are usually bacteriostatic
  • binding of erythromycin inhibits binding of the other 50S ribosome-binding antibiotics (chloramphenacol, streptogramins and clindamycin)
  • this indicates that the binding site is the same or closely associated
• selectivity of macrolides

  • the topography of 50S ribosomal subunit of bacteria is different from that of the 60S ribosomal subunit of mammals
  • macrolides do not bind tightly to the 60S subunits of mammals
• clarithromycin

  • 6-OH blocked by methyl group which prevents the spiroketal formation
  • chemically more stable
  • leading to a higher plasma level
  • the side effect of GI cramps is reduced

  
• azithromycin

  • a basic N-methyl group has been inserted btwn C9 and C10 and the carbonyl moiety is eliminated, which prevents the spiroketal formation
  • chemically more stable, thus a higher drug level in plasma
  • a considerably longer plasma half-life due to greater tissue penetration and retention
  • significant post-antibiotic effect
  • once a day dosing
  • more active against gram negative bacteria erythromycin and clarithromycin

  
• mechanisms of resistance of macrolides

  • decreased binding: plasmid-mediated expression of an RNA methylase
  • an adenine group in one rRNA strand of the 50S subunit is methylated
  • methylation of the adenine decreases the binding of erythromycin
  • cross resistance occurs to other macrolides, linconsamide and streptogramin B (MLSB resistance)
  • this is the most important mechanism of resistance
  • induction of efflux pumps
  • induction of an esterase enzyme (lactonase) that hydrolyzes the lactone ring and thus inactivates the macrolides
  • chromosomal mutations that alter a 50S ribosomal protein
• telithromycin - a ketolide

  • semisynthetic derivatives of erythromycin
  • 3-keto group in place of a glyco (a-L-cladinose) residue
  • a substituted carbamate at C11 - C12
  • less susceptible to MLSB and efflux-mediated mechanisms of resistance
  • similar spectrum of activity as compared to macrolides but more active against a number of macrolide-resistant gram positive strains

  
• protein synthesis inhibitors affected by MLSB

  • macrolides:
  • erythromycin
  • clarithromycin
  • azithromycin
  • linconsamides: clindamycin
  • streptogramin B: quinupristin
• clindamycin

  • MOA and basis of selective toxicity
  • similar to that of macrolides
  • it binds to the same site on 50S ribosomal subunits and inhibits protein synthesis in the same manner as erythromycin
  • weak base but more lipophilic than lincomycin and has better oral absorption (~90%)
  • less painful to take via injection than erythromycin

  
• clindamycin (cont.)

  • spectrum of activity similar to that of macrolides
  • works well for gram positive bacteria
  • a good option for pts hypersensitive to beta-lactams
  • GI complaint is the major adverse effect
  • eg: pseudomembranous colitis by Clostridium difficile
  • excellent activity against Propionibacterium acnes when applied topically to comedones; white colored
• clindamycin resistance

  • clindamycin is not a macrolide and does not have complete cross resistance to the macrolides
  • 1) cross resistance d/t the rRNA methylation (MLSB) does occur w/ clindamycin
  • 2) resistance d/t the macrolide exporter or the macrolide hydrolase (esterase) does not occur to clindamycin