beta-lactams

• structure of beta lactam antibiotics

  • the strained 4 membered ring makes the amid bond less stable and more reactive as an acylator
  • the C=C double bond in cephems or carbapenems also contribute the reactivity
• mechanism of beta lactam antibiotics - summary

  • beta lactam antibiotics inhibit the final step of cell wall synthesis: glycopeptide cross linking
  • beta lactam antibiotics inhibit transpeptidase enzymes (penicillin binding proteins; PBPs) that are responsible for the cross linking of the glycopeptide polymer chains of the cell wall
• mechanism of beta lactam antibiotics - summary (cont.)

  • without cross linking, the cell walls are not strong enough to contain the high osmotic pressure of the bacterial cell
  • resulting in ruptures of the membrane and cell death
  • inhibition of the transpeptidases is due to the covalent acylation of enzyme by the beta lactam ring of these drugs
• basis of selective toxicity

  • mammalian cells do not have cell walls
  • PBP's are not needed in mammalian cells
  • mammalian cells do not have D-amino acids
  • beta lactam antibiotics are unlikely to interfere w/ mammalian proteases or peptidases which cleaves protiens/peptides composed of L-amino acids
• why so many beta lactam antibiotics?

  • to have desirable pharmacokinetics/stability properties
  • ex: orally available, urine tract infections, GI tract infections, meningitis, serious systemic infections, etc.
  • to fight against different strains of bacteria
  • ex: different strains' PBP have different binding properties
  • to fight drug resistance
  • to minimize adverse effects
• penicillin binding proteins in E. coli

  • PBP 1a and PBP 1b
  • transpeptidases involved in peptidoglycan synthesis associated w/ cell elongation
  • inhibition results in spheroplast formation and rapid cell lysis
  • PBP 2
  • transpeptidase invovled in maintaining the rod shape of bacilli
  • inhibition results in ovoid/round forms that undergo delayed lysis
  • PBP 3
  • transpeptidase required for septum formation during cell division
  • inhibition not lethal to bacilli
• penicillin binding proteins in E. coli (cont.)

  • PBP 4, 5, 6
  • carboxypeptidases for the hydrolysis of D-alanine-D-alanine terminal peptide bonds of the cross linking peptides
  • Inhibition not lethal to the bacilli
  • 4 PBP's have been found in S. aureus
  • PBP's in different bacteria strains may be different
• major mechanism of resistance to beta lactam antibiotics

  • mutations of porins in gram negative bacteria which decrease drug penetration
  • expression of beta lactamases that degrade the antibiotics (most common)
  • mutations of PBP's which decrease their binding w/ the antibiotics
• stability of the beta lactam ring: how it can be decreased

  • by beta lactamases --> the major mechanism of resistance against beta lactam antibiotics
  • catalyzed by low pH as in gastric acid
  • thus decreasing or eliminating oral bioavailability
  • catalyzed by alkaline pH
  • by primary amino groups commonly seen in drugs
  • ie, aminoglycosides, amine group in some beta lactam antibiotics such as ampicillin
  • a few by endogenous peptidase
• long acting, injectable penicillin G

  • half life of penicillin G: ~ 30 min
  • repository preparations of penicillin G - penicillin G procaine (WYCILLIN, etc) and penicillin G benzathine (BICILLIN L-A, PERMAPEN)
  • slow release from the area of injection, relatively low but persistent concentrations of the antibiotic in the blood
  • aqueous suspension of the slightly soluble crystalline salts of Pen G w/ an amine-type local anesthetics, virtually painless injection
• summary of the structure-activity relationship of penicillins

  • the beta lactam ring is essential for antibiotic activity, more stain on the ring increases its acylation reactivity but decrease its stability
  • the 2-carboxylate mimics the C-terminus of D-ala-D-ala and is essential for the PBP binding and thus the antibiotic activtiy
  • the extensive steric hindrance d/t the "goat" branching pattern next to the carbonyl of the side chain (as seen in methicillin and nafcillin) hinders degradations by many beta lactamases
• summary of the structure-activity relationship of penicillins (cont.)

  • an electron-withdrawing group (eg, electron deficient aromatic rings or protonated amines) at the carbon next to the carbonyl of the side chain increases the acid stability of the penicillin, and therefore improves oral bioavailability
  • hydrophilicity on the acyl side chain contributes to activity against gram negative bacteria, d/t better binding of PBPs of gram negative bacteria and/or better permeation through porins
  • hydrophobicity on the acyl side chain improves binding to PBPs of many gram positive bacteria
• summary of the structure-activity relationship of penicillins (cont.)

  • zwitter ion type penicillin are substrates of intestinal dipeptide transporters, which increase their oral absorption
  • zwitter ions also pass porins better
  • more hydrophobic ester prodrugs improve the bioavailability of the parent drug
• examples of combinations of a penicillin and beta lactamase inhibitor

  • amoxicillin-clavulanate (augmentin, tablet)is effective in vitro and in vivo for beta lactamase producing strains of staphylococci, H. influenzae, gonococci, and E. coli
  • amoxicillin-clavulanate plus ciprofloxacin: effective oral treatment for low-risk, febrile pts w/ neutropenia from cancer therapy
  • other examples of combinations (parenteral use):
  • ticarcillin-clavulanate (timentin)
  • ampicillin-sulbactam (unasyn)
  • piperacillin-tazobactam (zosyn)
• monobactams: beta-lactams w/ no second fused ring

  • orally inactive
  • is stable to and can inactivate beta-lactamases
  • -SO3- mimics the function of C3-COOH in penicillins and cephalosporins but more electron-withdrawing to the lactam ring
  • specifically designed and synthesized against gram negative bacteria
  • allergy reported but cross-allergies w/ penicillins or cephalosporins are not common

  
• prosepctus

  • therapy w/ beta-lactam antibiotic is dynamic
  • the prevalence of bacterial resistance to these agents continues to rise, while new and more effective agents are being released for clinical use
  • ladder-like therapeutic protocols have been established to treat infectious diseases and to limit the further development of resistance