1 / 21

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.

priscilla-boyd
Download Presentation

Drugs that Inhibit Cell wall synthesis

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related