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

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3 Penicillin Family Amdinocillin Ampicillin Augmentin* Azlocillin Carbenicillin Cloxacillin Cyclacillin Dicloxacillin Floxacillin Amdinocillin Ampicillin Augmentin Azlocillin Carbenicillin Cloxacillin Dicloxacillin Amoxicillin Methicillin Mezlocillin Nafcillin Oxacillin Piperacillin Sulbactam (beta-lactamase inhibitor) Ticarcillin Timentin* Methicillin Mezlocillin Nafcillin Oxacillin Piperacillin Sulbactam Ticarcillin * Combo with beta-lactamase inhibitor

4 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

5 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

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

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9 lactames-mecanisme-action gifhttp:// lactames-mecanisme-action gif wuerzburg.de/ak_engel/Sebastian/Bilder/diplom5.gif D-Ala- D-Ala dipeptide Beta-Lactam reaction with transpeptidase

10 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

11 Vancomycin, a glycopeptide

12 Mechanism of vancomycin vancomycin Binds to peptide with high affinity via 5 hydrogen bonds

13 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. acitracin/bacitracin2.gif

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15 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

16 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

17 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. – proposes spread of resistance in animal feedhttp://

18 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

19 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

20 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

21 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