Antibiotic Mechanisms of Action
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Mechanism of action of major antibiotic classes including betal lactam agents, aminoglycosides, macrolides, tetracyclines, quinolons, vancomycin, oxazolidionons. Detailed review and illustrations
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Antibiotic Mechanisms of Action
- 1. Bacterial Structure and Mechanisms of Antimicrobial Action 1
- 2. Bacteria • Bacteria are prokaryotes – They are cells – They lack nuclei • There are two professional viewpoints regarding the general, overall classification of prokaryotes: – Some biologists support the concept that they constitute two domains: Archaea and Eubacteria – Other biologists classify them into two kingdoms, Archaebacteria and Eubacteria • Most are very small – 0.5 – 1.0 mm in diameter
- 3. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Inhibition of cell wall synthesis • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis • Inhibition of metabolic pathways • Interference with cell membrane integrity
- 5. BASIC SHAPES OF EUBACTERIA SPHERICAL ROD-SHAPED SPIRILLA
- 6. Gram stains and Morphology Courtesy Loyola University
- 9. Prokaryotic Organization • No nucleus • DNA held in nucleoid • Cytoplasm dense: – Ribosomes – Storage granules – Limited membranes • Plasma membrane • Corkscrew flagellum • Cell wall is complex – Outer membrane – Peptidoglycan layer – Capsule – Pili extend from cytoplasm
- 10. Prokaryotes • Lack nuclei • Typically lack or have very few internal membranes • Cytoplasm contains ribosomes, storage granules that hold glycogen, lipid, or phosphate compounds • Metabolic enzymes are associated with the plasma membrane, especially where it is infolded to form limited internal membranes – such membranes are generally referred to as a mesosome • The plasma membrane interacts with the cytoplasm in signaling functions • Motile bacteria have a corkscrew flagellum
- 11. INHIBITION OF CELL WALL SYNTHESIS 11
- 12. Cell Walls • Provides support for cell • Protects against osmotic shock – Most bacteria well adapted to hypotonic conditions – Most bacteria grow poorly in hypertonic conditions; hence jams, salted foods prevent bacterial growth • Cell wall composition unique to bacteria – Eubacterial cell wall made of peptidoglycan • Complex of polymerized amino sugars and short polypeptides • Is really one polymer surrounding the cell
- 13. Gram-positive and Gram-negative Cell Walls
- 14. 14 Gram –ve Gram +ve LPS Peptidoglycan Cell membrane
- 15. 15 Gram’s +ve Bacteria Gram’s -ve Bacteria
- 16. Cell Wall Structure: Gram Positive Bacterium 16
- 17. Cell Wall Structure: Gram Negative Bacterium 17
- 18. Courtesy of Southern Illinois University Medical Microbiology
- 20. Inhibition of Cell wall synthesis
- 21. Inhibition of Cell Wall Synthesis • Antimicrobials that interfere with the synthesis of cell wall (peptidoglycan) do not interfere with eukaryotic cell – Due to the lack of cell wall in animal cells and differences in cell wall in plant cells • These drugs have very high therapeutic index – Low toxicity with high effectiveness • Antimicrobials of this class include – β lactam drugs – Vancomycin – Bacitracin
- 23. Présentation 23 b-lactams action mode Antibiotics Penicillin binding proteins
- 24. (Cell membrane) (Peptidoglycan cell wall) Penicillin inactivates the transpeptidases by covalently bonding to the serine residues within the active site Bonding is by acetylation Transpeptidases (Penicillin Binding Proteins) S O
- 25. Competitively inhibits function of penicillin-binding proteins Inhibits peptide bridge formation between
- 26. The weakness in the cell wall causes the cell to lyze
- 27. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • The weakness in the cell wall causes the cell to lyze. • Penicillins and cephalosporins are considered bactericidal. • Penicillins are more effective against Gram+ bacteria. This is because Gram + bacteria have penicillin binding proteins on their walls.
- 28. The Cephalosporins • Chemical structures make them resistant to inactivation by certain β-lactamases • Tend to have low affinity to penicillin-binding proteins of Gram + bacteria, therefore, are most effective against Gram – bacteria. • Chemically modified to produce family of related compounds – First, second, third and fourth generation cephalosporins
- 29. Vancomycin • Inhibits formation of glycan chains – Inhibits formation of peptidoglycans and cell wall construction – Does not cross lipid membrane of Gram - • Gram - organisms innately resistant • Important in treating infections caused by penicillin resistant Gram + organisms • Must be given intravenously due to poor absorption from intestinal tract • Acquired resistance most often due to alterations in side chain of NAM molecule – Prevents binding of vancomycin to NAM component of glycan
- 31. N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-alaCell membrane Cell wall Transpeptidases (PBP’s)
- 32. N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala
- 33. N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala N-acetylglucosamine N-acetylmuramic acid d-ala L-glu Lys d-ala d-ala Mechanism of action of Vancomycin Vancomycin blocks cell wall synthesis By binding to the d-alanyl-d-alanine site on the growing peptidoglycan chain
- 34. • Bacitracin – Interferes with transport of peptidoglycan precursors across cytoplasmic membrane – Toxicity limits use to topical applications – Common ingredient in non-prescription first-aid ointments MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS
- 37. Inhibition of Protein Synthesis • Structure of prokaryotic ribosome acts as target for many antimicrobials of this class – Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity • Drugs of this class include – Aminoglycosides – Tetracyclins – Macrolids – Chloramphenicol
- 38. Inhibition of Protein Synthesis
- 40. Aminoglycosides
- 41. Aminoglycosides
- 42. Tetracyclines
- 43. Macrolides
- 44. Macrolides
- 46. Inhibition of Nucleic Acid Synthesis 46
- 47. 47 Fluoroquinolones: Inhibit action of topoisomerase DNA gyrase Rifamycins: Block prokaryotic RNA polymerase Block initiation of transcription
- 48. • Inhibit action of topoisomerase DNA gyrase – Topoisomerase maintains supercoiling of DNA • Effective against Gram + and Gram - • Examples include – Ciprofloxacin and ofloxacin • Resistance due to alteration of DNA gyrase Fluoroquinolones
- 49. Topoisomerase
- 50. Rifamycins • Block prokaryotic RNA polymerase – Block initiation of transcription • Rifampin most widely used rifamycins • Effective against many Gram + and some Gram - as well as members of genus Mycobacterium • Primarily used to treat tuberculosis and Hansen’s disease as well as preventing meningitis after exposure to N. meningitidis • Resistance due to mutation coding RNA polymerase – Resistance develops rapidly
- 53. Sulfonamides • Group of related compounds – Collectively called sulfa drugs • Inhibit growth of Gram + and Gram - organisms – Through competitive inhibition of enzyme that aids in production of folic acid • Structurally similar to para-aminobenzoic acid – Substrate in folic acid pathway • Human cells lack specific enzyme in folic acid pathway – Basis for selective toxicity • Resistance due to plasmid • Plasmid codes for enzyme that has lower affinity to drug
- 54. • Inhibits folic acid production – Interferes with activity of enzyme following enzyme inhibited by sulfonamides • Often used synergistically with sulfonamide • Most common mechanism of resistance is plasmid encoded alternative enzyme – Genes encoding resistant to sulfonamide and trimethoprim are often carried on same plasmid Trimethoprim
- 56. Interference with cell membrane integrity • Polymixn B most common • Binds membrane of Gram - cells – Alters permeability • Leads to leakage of cell and cell death – Also bind eukaryotic cells but to lesser extent
- 57. Daptomycin’s Mechanism of Action • Irreversibly binds to cell membrane of Gram- positive bacteria – Calcium-dependent membrane insertion of molecule • Rapidly depolarizes the cell membrane – Efflux of potassium – Destroys ion-concentration gradient
- 59. Bacterial Toxins • Not secreted but are components of the cell wall • Affect host when released from dead bacteria • Can bind macrophage, cause the release of fever-inducing agents • Resistant to heating
- 61. 61
- 64. Exotoxins • Pathogenic bacteria can produce exotoxins, which increase their success but tend to be very damaging to the host – Often the toxin, not the bacterial infection, is most dangerous – Examples: • Diphtheria toxin • Botulism toxin 64
- 65. Summary of Virulence Determinants Of Staphylococcus aureus • http://textbookofbacteriology.net/staph.html http://textbookofbacteriology.net/staph.html
- 67. 67
- 68. Capsules and Pili • Many bacteria secrete a capsule, or slime layer – Used to attach, prevent phagocytosis – Can be used to enhance infective bacteria • Pili are hair-like appendages – Allow attachment to surfaces – Are sometimes involved in bacterial conjugation (sexual activity that involves the transfer of DNA)
- 69. The Bacterial Flagellum • Rotates • Is corkscrew-shaped • Three parts: – Basal body – Hook – Filament (made of one protein: flagellin) • Cell uses ATP to pump protons out • Protons diffuse through membrane at basal body • Breakdown of gradient converted to rotation
- 70. Bacterial Chromosome • Bacteria have a circular genomic DNA molecule - – Single chromosome – ~1000X longer than cell if stretched out • Also have plasmids – Small, circular DNA fragments – Can replicate independently of the genomic DNA or be integrated into genomic DNA – Carry genes for resistance, for genetic exchange or for enzymes
- 71. Bacterial Sexual Reproduction • Most simply put, sex is transfer of genetic information. • Three mechanisms known for bacterial sexual reproduction: – Transformation • Bacteria take up DNA from environment • Griffith’s 1928 experiment with S and R bacteria showed that DNA was heritable substance – Transduction • Genes are transferred through phage (next slide) – Conjugation • Two cells of opposite mating type come together, form pili bridges bridges through which DNA is transferred
- 72. Conjugation of E. coli hfr: high frequency recombination
- 73. 73
- 74. MECHANISMS OF ACTION OF ANTIBACTERIAL DRUGS • Inhibition of cell wall synthesis • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis • Inhibition of metabolic pathways • Interference with cell membrane integrity