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Mechanism of action of antibiotics

Mechanism of action of antibiotics. The Sites of Activity in a Bacterial Cell for Various Antibiotics. Inhibition of bacterial cell wall. Cell Wall Biosynthesis. Stage I: Precursor formation Resulting in the production of the basic cell building block (UDP-acetylmuramyl-pentapeptide)

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Mechanism of action of antibiotics

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  1. Mechanism of action of antibiotics

  2. The Sites of Activity in a Bacterial Cell for Various Antibiotics

  3. Inhibition of bacterial cell wall

  4. Cell Wall Biosynthesis Stage I: Precursor formation Resulting in the production of the basic cell building block (UDP-acetylmuramyl-pentapeptide) Take place in the cytoplasm Cycloserine inhibits the terminal reactions in this stage

  5. Stage I

  6. Stage I

  7. Stage I

  8. Stage I

  9. Stage I

  10. Stage I

  11. Cell Wall Biosynthesis Stage II: formation of a linear peptidoglycan The precursor unit is carried from inside to outside A number of modifications occur and the units are linked covalently to preexisting cell wall Vancomycin and bacitracin act during this stage

  12. Stage II

  13. Stage II

  14. Stage II

  15. Stage II

  16. Cell Wall Biosynthesis Stage III: Crosslinking of the peptidoglycan Take place entirely outside the cell membrane The transpeptidase (the crosslinking enzyme) and other enzymes are inhibited by penicillins and cephalosporins

  17. Stage III

  18. Stage III

  19. 2. Drugs That Disrupt Cell Membrane Function A cell with a damaged membrane dies from a disruption in metabolism or lysis. These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes. Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria • Grammacidin forms bimolecular channel by association of two molecules of formyl end, forming hydrophilic pore through bacterial cell membrane leading to loose of H +, K + and water causing electrolyte imbalance and death

  20. Disruption of cell membrane • Disruption of fungal membrane through binding with the sterol component of fungus cell membrane (Eucaryotic cell) causing a hydrophilic pores in the membrane leading to loss of H +, K + and water causing to electrolyte Imbalance and death e.g. polyene antibiotic as nystatin, amphotericin B

  21. Adverse Effects of Polymyxin • Tachycardia • Eosinophilia • Fever • Nephrotoxicity and Neurotoxicity • Skin exanthemata • Urticaria

  22. DNA Structure

  23. Nitrogen Bases

  24. Nucleosides

  25. Nucleotides

  26. Polynucleotide

  27. DNA Structure

  28. DNA Nitrogen base, ribose, phosphate Nucleotide Polynucleotide Nucleosome (DNA + Histone) Chromatin Chromosome (1 centromere, 2 telomeres, several replication origins)

  29. Replication Origins Bacterial chromosome has one, whereas each eukaryotic chromosome has many Unique DNA segments contain multiple short repeated AT-rich sequences which recognized by multimeric origin-binding proteins that play a key role in assembling DNA polymerases and other replication enzymes at the sites where replication begins

  30. DNA Replication Starts at replication origin Helicase (unwinding of DNA) (replication fork) single stranded DNA binding protein (SSB) Leading and lagging strands RNA Primase (placing of RNA primers)

  31. DNA Replication • DNA Polymerase (the major work, 1000 nucleotides/sec) • RNA Primase (formation of Okazaki fragments) • Exonuclease (breakdown of RNA primers), and DNA polymerase replace them with DNA nucleotides • DNA Ligase (filling the gaps by inserting phosphate)

  32. Inhibition of RNA synthesis (inhibition of transcription) through inhibition of RNA polymerase enzyme. • Antitumerantibiotics actinomycin, doxorubicin, and mithramycin bind to DNA inhibiting DNA templing and inhibiting RNA polymerase enzymes. • Rifamycins bind to RNA polymerase enzyme so inhibiting its activity • Inhibition of DNA synthesis by inhibition of either: • DNA gyrase enzyme thus inhibits DNA synthesis e.g. Novobiocin and nalidixic acid. • Covalently binds between DNA single strands, leading to inhibition of DNA synthesis e.g. Anti-tumer AB's as Bleomycin and Mitomycin.

  33. Protein Synthesis Transcription Translation Initiation Elongation Termination

  34. Transcription Starts at promoter region (SIGMA = start) Helicase Template (antisense) strand Informational (coding, sense) strand DNA-dependent RNA polymerase RHO = stop

  35. Transcription • mRNA formation (immature) (pre-mRNA) • Methyl guanosine capping (5’) (helps ribosomes attach for translation) • Polyadenylation (up to 200 adenosine ribonucleotides) (3’) (helps transport the mRNA out of the nucleus and may stabilize the mRNA against degradation in the cytoplasm) • Splicing (spliceosomes) • Mature RNA formation

  36. RNA mRNA 250-10,000 nucleotides tRNA 75-90 nuceotides, most abundant, up to 64 forms (20 amino acids)

  37. RNA • rRNA • Ribosome (60% rRNA + 40% protein) • Svedberg factor (s) • Prokaryotes 70s (50s + 30s) • Eukaryotes 80s (60s + 40s) • P (peptidyl) and A (amino acyl tRNA) sites

  38. Translation Initiation Elongation (peptidase, translocase) Termination

  39. Genetic Codes

  40. The Action of Antimicrobial Drugs

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