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Antibiotics

Antibiotics. Mechanism of Action and Resistance. Antimicrobial Action and Resistance. Definition, concept of selective toxicity Targets and mechanisms of action of the major antibacterial agents Mechanisms of resistance to antibacterial agents Evolution and spread of antibiotic resistance.

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Antibiotics

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  1. Antibiotics Mechanism of Action and Resistance

  2. Antimicrobial Action and Resistance • Definition, concept of selective toxicity • Targets and mechanisms of action of the major antibacterial agents • Mechanisms of resistance to antibacterial agents • Evolution and spread of antibiotic resistance

  3. Antimicrobials • Low molecular weight substances active against microorganisms at low concentrations • Historically two types • Antibiotic - microbial origin • Antimicrobial - chemically synthesized • Antimicrobial chemotherapy

  4. Selective toxicity • Active against bacteria not host • Targets unique to microorganism • peptidoglycan • Metabolic pathway absence in vertebrates • folate biosynthesis • Microbial enzyme has higher affinity than vertebrate enzyme • dihydrofolate reductase • Structural differences between bacterial and eucaryotic component • ribosome, chromosomes • Antibiotic is only actively transported or activated by microbe • tetracyclines, amino glycosides, metronidazole

  5. Action of antimicrobial • Bacteriocidal • Irreversible • May or may not cause lysis • Bacteriostatic • Reversible • Generally characteristic of antibiotic • Dose • Organism

  6. Sites of action of main antibiotics Protein synthesis DNA biosynthesis and replication Peptidoglycan biosynthesis

  7. Sites of antimicrobial action • Peptidoglycan synthesis • Protein synthesis • Nucleic acid synthesis • DNA replication • Transcription • Cytoplasmic membrane integrity

  8. Peptidoglycan

  9. Biosynthesis of Peptidoglycan • Synthesize precursors in cytoplasm • Transport of precursors across cell membrane • Addition of precursors to peptidoglycan • Cross-linking of peptidoglycan chains

  10. NAG NAM peptide Biosynthesis of Peptidoglycan Synthesize precursors in cytoplasm Cytoplasm Cytoplasmic membrane Transport of precursors across cell membrane Addition of precursors to peptidoglycan Cell wall Cross-linking of peptidoglycan chains

  11. NAG NAM Cycloserine peptide Bacitracin Glycopeptides b-Lactams Glycopeptides Biosynthesis of Peptidoglycan Synthesize precursors in cytoplasm Transport of precursors across cell membrane Addition of precursors to peptidoglycan Cross-linking of peptidoglycan chains

  12. Biosynthesis of Peptidoglycan • Synthesize precursors in cytoplasm • Cycloserine • Transport of precursors across cell membrane • Bacitracin • Addition of precursors to peptidoglycan • Glycopeptides • Cross-linking of peptidoglycan chains • b-lactams, glycopeptides

  13. Action of -lactams

  14. Effect of penicillin on a bacterium

  15. Protein synthesis inhibitors Translation

  16. Inhibit initiation Cause misreading of mRNA Protein synthesis inhibitors (PSI): Aminoglycosides Aminoglycosides, eg. Streptomycin, Gentamicin, Amikacin NB. The only protein synthesis inhibitors that are bactericidal

  17. Inhibit peptidyl transferase Chloramphenicol Macrolides Lincosamides Inhibit translocation Macrolides Lincosamides PSI: Chloramphenicol, macrolides and lincosamides

  18. PSI: Tetracyclines

  19. P A mRNA 5’ 3’ Protein synthesis inhibitors Nascent polypeptide Chloramphenicol 50S Macrolides, lincosamides Tetracyclines Aminoglycoside 30S Direction of translation 70S ribosome

  20. Action of sulphonamides and trimethoprim • Block the biosynthesis of folic acid • Folic acid is a co-factor in metabolism • Eg, needed in nucleic acid biosynthesis Selective toxicity: • Most bacteria must synthesize folate de novo • They cannot use exogenous folate • Vertebrates cannot synthesize folate, it is a vitamin

  21. Sulphonamides Trimethoprim Dihydropteroate Synthetase (DHPS) Dihydrofolate Reductase (DHFR) Action of sulphonamides and trimethoprim Para-amino benzoic acid (PABA) Dihydropteroate Dihydrofolate Tetrahydrofolate Nucleic acid synthesis

  22. Inhibitors of DNA replication • Quinolones and 4-fluoroquinolones • Naladixic acid, enrofloxacin, ciprofloxacin • Prevents introduction of negative supercoils

  23. Other antibiotics and their action • Rifamycins • Transcription • E.g. Rifampicin – Imp. TB. • Polymyxins • Cell membrane, antimicrobial peptides • Nitroimidazoles • Disrupts DNA • Only active against anaerobes and protozoa • Metronidazole • Banned in food animals

  24. Anti-fungals Polyene antifungals Amphotericin B , Nystatin Bind ergosterol disrupt cell membrane Cell wall Cell membrane Imidazoles Miconazole, clotrimoxazole, Ecoconazole, ketoconazole Inhibit ergosterolbiosynthesis Nucleus 5-flucytosine Inhibit DNA & RNA biosynthesis Microtubules Griseofulvin Inhibit microtubule assembly

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