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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.

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Drugs that Inhibit Cell wall synthesis

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  1. 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

  2. Penicillin Family • AmdinocillinAmpicillinAugmentin*AzlocillinCarbenicillinCloxacillinCyclacillinDicloxacillinFloxacillin AmoxicillinMethicillinMezlocillinNafcillinOxacillinPiperacillinSulbactam(beta-lactamase inhibitor)TicarcillinTimentin* * Combo with beta-lactamase inhibitor http://www.wheelessonline.com/ortho/penicillin_family

  3. 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

  4. 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

  5. Peptidoglycan Synthesis-2 • new NAM-NAG unit attached, autolysins cut old wall • crosslinking completed

  6. 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

  7. 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

  8. Vancomycin, a glycopeptide http://www.chemicalforums.com/index.php?page=molecules

  9. Mechanism of vancomycin vancomycin Binds to peptide with high affinity via 5 hydrogen bonds http://www.ratsteachmicro.com/Assets/Antibiotics_combined/vancomycin.gif

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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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