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Drugs that Inhibit Cell wall synthesis. Beta-lactams Penicillin family Cephalosporin family Carbapenems and Monobactams Β -lactamase inhibitors Vancomycin Bacitracin These drugs are bactericidal Failure of the cell wall results in death. Penicillin Family.

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drugs that inhibit cell wall synthesis
Drugs that Inhibit Cell wall synthesis
  • Beta-lactams
    • Penicillin family
    • Cephalosporin family
    • Carbapenems and Monobactams
    • Β-lactamase inhibitors
  • Vancomycin
  • Bacitracin
  • These drugs are bactericidal
    • Failure of the cell wall results in death
penicillin family
Penicillin Family
  • AmdinocillinAmpicillinAugmentin*AzlocillinCarbenicillinCloxacillinCyclacillinDicloxacillinFloxacillin

AmoxicillinMethicillinMezlocillinNafcillinOxacillinPiperacillinSulbactam(beta-lactamase inhibitor)TicarcillinTimentin*

* Combo with beta-lactamase inhibitor

http://www.wheelessonline.com/ortho/penicillin_family

development of beta lactam families
Development of Beta-lactam families
  • Target different species
    • Not all drugs can pass through Gram – OM
    • “Penicillin binding proteins” (PBPs) vary
    • Specificity of beta-lactamases varies
    • Beta-lactam ring sensitive to hydrolysis; improved acid stability for oral administration
  • Thus drugs differ
    • In organisms that they affect
    • General pharmacokinetics, administration
    • Type and extent of resistance against
peptidoglycan synthesis 1
Peptidoglycan Synthesis-1
  • NAM and peptide with D-ala connected
  • Attached to lipid carrier: bactoprenol-phosphate
  • NAG added (UDP-NAG) to complete unit
  • NAG-NAM-peptide transported through cell membrane to cell wall
peptidoglycan synthesis 2
Peptidoglycan Synthesis-2
  • new NAM-NAG unit attached, autolysins cut old wall
  • crosslinking completed
slide9

Beta-Lactam reaction with transpeptidase

D-Ala- D-Ala dipeptide

http://www.antiinfectieux.org/antiinfectieux/Assets/PLS/Beta-lactames/beta-lactames-mecanisme-action-2-600.gif http://www-organik.chemie.uni-wuerzburg.de/ak_engel/Sebastian/Bilder/diplom5.gif

consequences of mode of action
Consequences of mode of action
  • Beta-lactam reacts with serine in active site
    • Irreversible binding, inactivates enzyme
    • Also inactivates drug, used up in reaction
  • Target is in cell wall
    • External beta-lactamases destroy drug before target is reached
slide11

Vancomycin, a glycopeptide

http://www.chemicalforums.com/index.php?page=molecules

mechanism of vancomycin
Mechanism of vancomycin

vancomycin

Binds to peptide with high affinity via 5 hydrogen bonds

http://www.ratsteachmicro.com/Assets/Antibiotics_combined/vancomycin.gif

bacitracin
Bacitracin

Peptide antibiotic

Isolated from Bacillus from a patient named Tracy.

With divalent cation, binds to bactoprenol-pyrophosphate, prevents dephosphorylation of carrier, blocks PG biosynthetic pathway.

http://smccd.net/accounts/case/biol230/bacitracin/bacitracin2.gif

resistance to beta lactams
Resistance to beta-lactams
  • Beta-lactamases
    • Numerous types present among bacteria
    • Found on Gram – as well as Gram +
    • Coded for plasmids or by chromosomal genes
    • Some sensitive to beta-lactamase inhibitors, some not
  • Resistance in Gram - : failure to reach target
    • Passage through OM is through porins
    • Although porins are not highly selective, some drugs cannot pass or the porins become mutated
resistance to beta lactams 2
Resistance to beta-lactams-2
  • Failure to bind to target
    • Wide variety of bacteria, wide assortment of PBPs
    • Mutations occur in PBP genes
  • About MRSA
    • Staph aureus originally susceptible to penicillin, 1940s; by 1950s, no longer
    • About 40% of Staph aureus now resistant to methicillin and other beta-lactamse resistant drugs
    • Has acquired a gene for a PBP that poorly binds beta-lactams, causing resistance
resistance to vancomycin
Resistance to vancomycin
  • A cluster of genes that senses the presence of vancomycin, activates an enzyme that replaces the D-ala-D-ala dipeptide with D-ala-D-lactate.
    • Interesting evolutionary history
    • Gene cluster probably originated with producing streptomyces
    • Known to be present in Enterococci, probably passed by conjugation to Staph aureus.
    • http://www.medscape.com/viewarticle/473156 proposes spread of resistance in animal feed
pharmacokinetics
Pharmacokinetics
  • Beta-lactams differ greatly in
    • Route of administration (oral absorption)
    • Binding to serum proteins
    • Metabolism and extent of renal excretion
      • Tend to be excreted unchanged (good for treatment of urinary tract infections)
  • Benzathine penicillin, im injection
    • Half life of 14 days
    • Mainstay of health clinics for treatment of syphilis
about combinations
About combinations
  • Beta-lactamase inhibitors
    • Clavulanate, sulbactam, and tazobactam
    • Some have weak antibiotic activity alone
    • Bind to beta-lactamases and inhibit them
    • Beta-lactamase inhibitors paired with beta-lactam antibiotics which then do the heavy lifting
  • Typical example
    • Clavulanate + amoxicillin = Augmentin
toxicity
Toxicity
  • Beta-lactams show wide range
    • Diarrhea and other GI problems are most common
      • Problems with upsetting normal ecology
      • Most significant danger: pseudomembranous colitis caused by Clostridium difficile
    • Delayed type hypersensitivity much more likely than immediate type (IgE), fortunately
toxicity 2
Toxicity-2
  • Vancomycin
    • Hypersensitivity reactions with rash and hypotension
    • Ototoxicity, phlebitis
  • Bacitracin
    • Topically administered, few problems
    • Cannot be taken internally because of inhibition of sterol synthesis, nephrotoxicity