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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. - PowerPoint PPT Presentation
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1Drugs 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
2
3Penicillin Family
•AmdinocillinAmpicillinAugmentin*AzlocillinCarbenicillinCloxacillinCyclacillinDicloxacillinFloxacillin
AmoxicillinMethicillinMezlocillinNafcillinOxacillinPiperacillinSulbactam (beta-lactamase inhibitor)
TicarcillinTimentin*
http://www.wheelessonline.com/ortho/penicillin_family
* Combo with beta-lactamase inhibitor
4Development 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
5Peptidoglycan 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
6Peptidoglycan Synthesis-2
• new NAM-NAG unit attached, autolysins cut old wall
• crosslinking completed
7
8
9
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
D-Ala- D-Ala dipeptide
Beta-Lactam reaction with transpeptidase
10Consequences 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
11
http://www.chemicalforums.com/index.php?page=molecules
Vancomycin, a glycopeptide
12Mechanism of vancomycin
vancomycin
Binds to peptide with high affinity via 5 hydrogen bonds
http://www.ratsteachmicro.com/Assets/Antibiotics_combined/vancomycin.gif
13Bacitracin
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
14
15Resistance 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
16Resistance 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
17Resistance 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
18Pharmacokinetics
• 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
19About 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
20Toxicity
• 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
21Toxicity-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