aminoglycosides

• aminoglycosides antibiotics

  • the drug class consist of 7 different agents
  • streptomycin
  • gentamicin (our prototype drug)
  • tobramycin
  • amikacin
  • netilmicin
  • kanamycin
  • neomycin
  • most commonly used aminoglycosides in US:
  • gentamicin
  • tobramycin
  • amikacin
• general chemical features of aminoglycosides

  • contains 1,3-diaminoinositol moiety (critical for antibacterial activities), which links to other glyco residues to give oligosaccharide type molecules
  • positively charged at neutral pH
  • highly polar w/ numerous hydroxy groups
  • highly water soluble
• general PK/toxicity properties of aminoglycosides

  • minimal oral absorption
  • confined in GI tract if given orally
  • can be sued to treat infections in GI tract
  • eliminated mainly by renal excretion after parenteral administraiton
  • potential plasma accumulation and high toxicity in pts w/ impaired renal function
  • concentration dependent killing w/ significant PAE
  • renal toxicity and ototoxicity w/ delayed onset are major concerns for their use
• MOA of aminoglycosides - 1. penetration into bacteria cells

  • aminoglycosides enter the gram negative bacteria cells by diffusion across porins
  • followed by uptake by a transporter system that is dependent on energy and the cytoplasm membrane electrical potential
  • stronger binding w/ negatively charged proteoglycans of the thicker cell wall of gram positive bacteria decreases aminoglycosides' activites against gram positive bacteria
  • aminoglycosides generate defect bacterial proteins, which impair bacteria cytoplasm membranes and enhance further drug penetration
• MOA of aminoglycosides - 2. protein synthesis inhibition

  • aminoglycosides bind to the bacterial 30S ribosomal subunit and alter protein synthesis in three ways
  • block the initiation of protein synthesis
  • the abnormal initiation complexes are aborted
  • block the elongation (premature termination)
  • the shortened, non-funcitonal protein segments are released
  • cause the misreading of mRNA
  • incorporation of incorrect amino acids or missing of stop codons to generate "run-on" proteins
• MOA of aminoglycosides - 3. bacteriacidal effect

  • it is thought that the abnormal proteins/peptides are inserted into the bacteria's membrane
  • resulting sequentially in more aminoglycoside import, cell membrane leakage and eventual cell death
• mechanism of resistance to the aminoglycosides

  1. enzymatic inactivation of aminoglycosides

  • 9 different enzymes have been identified, including enzymes that acetylate the amino groups (amino acetyltransferases), enzymes that phosphorylate -OH groups (aminoglycoside phosphotransferases), and enzymes that conjugate the aminoglycosides w/ nucleotides (aminoglycoside nucleotidyltransferases)
  • this is the most important mechanism of resistance in clinical practice
• mechanism of resistance to the aminoglycosides (cont.)

  • 2. decreased transport
  • transporter protein for the active uptake of the aminoglycosides is mutated so that the drug molecules no longer bind, or the expression of the transporter protein is decreased or eliminated
  • cross resistance usually occurs
  • 3. point mutations occur in the proteins of the 30S ribosomal subunit that result in decreased binding of the aminoglycosides
  • more than one binding site is invovled so resistance to one aminoglycoside may not cross to the action of others
  • this mechanism is not of major clincial importance
• amilacin and netilmicin

  • most resilient to the inductible bacterial metabolic enzymes
  • thus should be reserved until resistance to the other aminoglycoside has developed
  • once resistance of these two drugs has developed, cross resistance to all other aminoglycosides antibiotics will occur
• structural features that hinder the enzymatic inactivation of aminoglycosides

  • amikacin
  • the long amine-substitution at N1 of diaminoinositol ring hinders the modifications at both neighboring and remote amino/hydroxy groups
  • netilmicin
  • ethyl substitution at N1 of diaminoinositol prevents the acetylation on the group
  • less hydroxy groups on glyco resides attached to the diaminoinositol ring
  • methyl group at 4'-C hinders modification of 4'-OH
• aminoglycosides are synergistic w/ the beta-lactam antibiotics

  • probable mechanisms:
  • 1) beta-lactam antibiotics cause membrane breaks that help aminoglycosides enter the cells
  • 2) aminoglycosides induce production of nonfuncitonal polypeptides that parition to and further permeate the bacterial cell membrane
  • 3) aminoglycosides decrease synthesis of proteins, including beta-lactamases, resulting in increased activity of the beta-lactam antibiotic
  • example: carbenicillin and gentamicin are commonly used in combination
• • aminoglycosides and beta-lactam antibiotics are not chemically compatible
  • do not mx them in the dosage form
  • the following chemical reaction will occur btwn the 2 agents, inactivating them both