Download Clostridium difficile

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
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Penicillin Family
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Amdinocillin
Ampicillin
Augmentin*
Azlocillin
Carbenicillin
Cloxacillin
Cyclacillin
Dicloxacillin
Floxacillin
Amoxicillin
Methicillin
Mezlocillin
Nafcillin
Oxacillin
Piperacillin
Sulbactam (beta-lactamase inhibitor)
Ticarcillin
Timentin*
* Combo with beta-lactamase inhibitor
http://www.wheelessonline.com/ortho/penicillin_family
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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
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Peptidoglycan Synthesis-1
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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
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• new NAM-NAG unit attached, autolysins cut old
wall
• crosslinking completed
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Beta-Lactam reaction with transpeptidase
D-Ala- D-Ala
dipeptide
http://www.antiinfectieux.org/antiinfectieux/Assets/PLS/Beta-lactames/betalactames-mecanisme-action-2-600.gif http://www-organik.chemie.uniwuerzburg.de/ak_engel/Sebastian/Bilder/diplom5.gif
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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
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Vancomycin, a
glycopeptide
http://www.chemicalforums.com/index.php?page=molecules
Mechanism of vancomycin
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vancomycin
Binds to peptide with
high affinity via 5
hydrogen bonds
http://www.ratsteachmicro.com/Assets/Antibiotics_combined/vancomycin.gif
Bacitracin
Peptide antibiotic
Isolated from Bacillus
from a patient named
Tracy.
http://smccd.net/accounts/case/biol230/b
acitracin/bacitracin2.gif
With divalent cation,
binds to bactoprenolpyrophosphate, prevents
dephosphorylation of
carrier, blocks PG
biosynthetic pathway.
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Resistance to beta-lactams
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• 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
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• 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
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• 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
• 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
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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
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Toxicity
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• 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
• 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
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