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Action of penicillins

Action of penicillins. 1. mode of action 2. family of β lactams 3. route of traverse across cell envelope. 1. Antibacterial agents. Cell wall Cell membrane Intracellular metabolism Nucleic acid biosynthesis Protein synthesis New targets: genomics. Selective toxicity.

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Action of penicillins

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  1. Action of penicillins 1. mode of action 2. family of β lactams 3. route of traverse across cell envelope

  2. 1. Antibacterial agents • Cell wall • Cell membrane • Intracellular metabolism • Nucleic acid biosynthesis • Protein synthesis • New targets: genomics

  3. Selective toxicity • Ability of a biological agent to inhibit or arrest a pathogen without injury to the host • unique targets in procaryotes • Bactericidal • kills • Bacteriostatic • inhibitory; host defences

  4. Antibiotic • Chemical substance produced by one spp • Inhibits in small amounts growth of another micro-organism • Discovery of penicillin • A. Fleming • benzylpenicillin • Penicillium notatum

  5. 2. β lactams • Constrained 4-membered structure = β lactam ring • Thiazolidine ring sulphur-containing 5- or 6-membered ring • Substututions: • free amino group: β lactam ring • free carboxyl group: thiazolidine ring

  6. β lactams • Penicillins ampicillin, amoxicillin, methicillin • Cephalosporins 1: cephalothin, cephaloridine, cephalexin 2: cephamandole, cefuroxime, cefaclor 3: cefotaxime, ceftriaxone, ceftazidine

  7. β lactams • Different properties to inhibit different m-o • Diffuse across OM / porins • Cleavage of β lactam ring • β lactamase  inactivated antibiotic • Targets: • enzymes of peptidoglycan biosynthesis • PBPs

  8. PBPs • Single target  multiple targets • Expt #1: • Growing E. coli + 14C-penicillin • Pen binds to target(s) • Collect cells; lysate; identify labelled material • SDS-PAGE / autoradiography • Multiple proteins – [14C-penicillin] • All 14C-proteins are in CM

  9. PBPs • Isolation: affinity chromatography • Inert matrix –[penicillin] • Expt #2: • Lysate of E. coli applied to matrix—[penicillin] • Some proteins bind to penicillin • Elute, assay in vitro activities • PBPs = penicillin-sensitive enzymes

  10. Penicillin-sensitive enzymes

  11. 3. Route across cell envelope • OM: porins • Periplasm: degrading enzymes • CM: enzymes of p/g assembly = PBPs

  12. Desirable properties • Penetrates OM via porins • Free diffusion • Hydrophilic compounds • Resist β lactamase • Bind with high affinity to targets = PBPs

  13. Infectious antibiotic resistance • β lactamase • Plasmid-encoded • Promiscuous • inter species transfer; intra species transfer • Proliferation of resistance elements • Selective advantage

  14. keywords • Micro-organisms • Streptomyces jumojeniensis, actinomycete • bacteria: Proteus vulgaris, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Bacteriodes fragilis

  15. keywords • Anti-microbials • Penicillins: ampicillin • Cephalosporins: cephamycin C, cefmetazole, cefalothin, cefazolin • Nitrocefin • Aminoglycosides

  16. keywords • Terms: • Soil samples, β lactamase, antibiotic activity, OM, cell wall, peptidoglycan, Gram-negative and Gram-positive, barrier layer, periplasm, MICs (minimum inhibitory concentrations: 3-13 and 100 μg/ml, vacuoles, blebs, spheroplasts, bacteriolysis, ghosts, snake-forms, indole-positive, opportunistic pathogen, septicemia, 7 PBPs in CM, PBP2- = spheres, PBP3- = filaments, t.s. phenotype, affinity for PBPs, autoradiography

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