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
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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• 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
• 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
• 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