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Lecture 02
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Lecture 02

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mechanism of antibiotics action

mechanism of antibiotics action

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  1. Bio 319: Antibiotics Lecture Two Topic: Characteristics of antibiotics and their classification Lecturer: Dr. G. Kattam Maiyoh13/02/2013 GKM/BIO319:Antibiotics/Lec. 02/Sem02/2013 1
  2. Brief overview• General aspects• Classification – Cidal vs. Static – Target organism – Spectrum of activity – Mechanism of action • Cell synthesis inhibitors – Beta lactams » Penicillins » cephalosporins13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 2
  3. General Aspects of antibiotics • Principle: Inhibit growth of bacteria without harming the host – Drug must penetrate body tissue to reach bacteria (exception: GI infection) (unique targets: cell wall, protein synthesis, metabolic pathways…) – Bacteria targeted must be within the spectrum of the Antibiotic – Drug can be bactericidal or bacteriostatic – Different agents can be combined for synergistic effect (Note: not all combinations are useful, e.g. cell wall synthesis inhibitors loose effectiveness when combined with bacteriostatic drugs) – Identification of the invasive microorganism necessary for optimal treatment • General side effect: Alteration in normal body flora – GI tract harbors symbiotic bacteria which are killed by antibiotic => resistant bacteria repopulate the niche = secondary or superinfection result (most common: overgrowth of Clostridium difficile)13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 3
  4. Classification of antibiotics• At the highest level, antibiotics can be classified as either bactericidal or bacteriostatic.• Bactericidals kill bacteria directly while bacteriostatics prevent cell division.• However, these classifications are based on laboratory behavior; in practice, both of these are capable of ending a bacterial infection.• The bactericidal activity of antibiotics may be growth phase dependent and in most but not all cases action of many bactericidal antibiotics requires ongoing cell activity and cell division for the drugs killing activity13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 4
  5. a. Static vs. Cidal•The graphs show the growth curves for abacterium treated with two drugs.•The upper curve shows the activity of abacteriostatic drug.•The bacterial growth resumes when thedrug is withdrawn. • Penicillins, aminoglycoside, vanconmyci•The cidal drug, shown in the lower n, bacitracin , the polymyxin, and colistin are bactericidal.graph, kills bacteria from the time ofadministration to the culture. • Tetracyline , Fusidic acid , Macrolides, Sulfonamides and sulfones on the other hand, are bacteriostatic.13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 5
  6. Classification of Antibiotics • Bacteriostatic vs. Bactericidal13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 6
  7. Target organism• Another method - according to which bacterial strains they affect:• For example; Staphylococcus, Streptococcus, or Escherichia coli,.13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 7
  8. Spectrum of activityMay also be classified based on spectrum of activity; 1. Broad spectrum 2. Narrow spectrum 3. Extended spectrum13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 8
  9. Antibiotic Spectrum of Activity • No antibiotic is effective against all microbes13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 9
  10. b. Based on action against the infecting organism13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 10
  11. Classification: Mode of action • Cell wall synthesis inhibitors • Injury to plasma membrane – Beta-lactams -polymyxin B (penicillins, cephalosporins, aztr - mystatin eonam, imipenem) - amphotericin B – Poly-peptides - miconazole (bacitracin, vancomycin) • Protein synthesis inhibitors • Inhibition of njucleic acid – Aminoglycosides replication and transcription – Tetracyclins – Macrolides - Quinolones – Chloramphenicol - Rifampin – Clindamycin • Inhibitors of essential metabolites (folate) – Sulfonamides – Trimethoprim13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 11
  12. Inhibitors of Cell Wall Synthesis13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 12
  13. Cell wall synthesis inhibitors Bacterial cell wall: Three types: • Gram-negative (e.g. E.coli, Salmonella) – Few peptidoglycan layers (Lipopolysaccheride) • Gram-positive (e.g. Staphylococci, Listeria) – Many peptidoglycan layers (Lipoteichoic acid) – Stains w/ crystal-violet/iodine • Acid-fast positive (Mycobacteria) – Cell wall contains waxy substance (Mycolic acid) – Stain w/ acid fast test (heating required)13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 13
  14. • There are three types – Gram-negative (e.g. E.coli, Salmonella) • Have few peptidoglycan layers • (stain safranin or fuchsin) – Gram-positive (e.g. E.coli, Staphylococci, Listeria • Have many peptidoglycan layers • stains with crystal violet • typically lack the outer membrane found in gram- ve. – Acid-fast Positive (Mycobacteria) • Cell wall contains waxy substance (Mycollic acid) • Stains with acid fast (heating required) 13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 14
  15. Antibiotics - Cell wall synthesis inhibitorsBeta-lactam antibiotics:1928 - Alexander Fleming observes the antibacterial effects of Penicillin1940 - Florey and Chain extract Penicillin13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 15
  16. The beta lactams • The β-lactam group of antibiotics includes an enormous diversity of natural and semi-synthetic compounds that inhibit several enzymes associated with the final step of peptidoglycan synthesis. • All of this enormous family are derived from a β - lactam structure: a four-membered ring in which the β -lactam bond resembles a peptide bond. • The multitude of chemical modifications based on this four-membered ring permits the astonishing array of antibacterial and pharmacological properties within this valuable family of antibiotics.13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 16
  17. The Beta-Lactams R – variable side chain Monobactam nucleus13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 17
  18. Penicillinase ( Lactamase) More when we discuss antibiotic resistance13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 18 Figure 20.8
  19. • Penicillium notatum produces the only naturally occurring agent – penicillin G or benzylpenicillin• Penicillium chrysogenum produces 6-aminopenicillanic acid, raw material for semi-synthetics13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 19
  20. Targets for beta lactams• The targets for β-lactam drugs are the penicillin binding proteins (PBPs), so called because they bind radioactive penicillin and can be detected by autoradiography of gels on which bacterial proteins have been separated electrophoretically.• The penicillin binding proteins have transpeptidase or carboxypeptidase activity and they act to regulate cell size and shape.• They are also involved in septum formation and cell division. Bacteria have several individual penicillin binding proteins, each with a separate function.• Conventionally these are numbered according to size, with PBP 1 as the largest protein.• The PBP 1 of one bacterium will not necessarily have the same function as the PBP 1 of a different organism.13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 20
  21. Target• The β-lactam antibiotics also stimulate the activity of autolysins.• These are enzymes that are responsible for the natural turnover of cell wall polymers to permit growth of the cells.• Under normal conditions, these enzymes produce controlled weak points within the peptidoglycan structure to allow for expansion of the cell wall structure.• This activity is stimulated by β-lactams, causing a breakdown of peptidoglycan and leading to osmotic fragility of the cell and ultimately to cell lysis.13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 21
  22. Penicillins - classification – Narrow spectrum – penicillinase sensitive – Narrow spectrum – penicillinase resistant – Broad spectrum penicillins – Extended-spectrum penicillins • Cephalosporines • Carbapenems • Monobactams • Vancomycin, Bacitracin13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 22
  23. Natural Penicillins• Penicillin G, Penicillin V13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 23
  24. Penicllins (general info.) • Derived from the fungus Penicillium • Attains therapeutic concentration in most tissues • However has poor CSF penetration • Renal excretion • Side effects: hypersensitivity, nephritis, neruotoxicity, plate let dysfunction13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 24
  25. Penicillins Inhibit transpeptidase required for cross-linking peptidoglycan chains Also inactivate an inhibitor of an autolytic bacterial enzyme => lysisNarrow spectrum – penicillinase (= β-lactamase) sensitive • Benzylpenicillin – Naturally occuring – Poor oral availability (sensitive to stomach acid) => given by injection – Active against gram-positive bacteria• Phenoxymethylpenicillin – Better oral availability (acid resistant)13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 25
  26. Narrow spectrum – penicillinase (= β-lactamase) resistant • Methicillin – Semisynthetic – Poor oral availability (only parenteral) – Active against gram-pos bacteria – Mostly used for Staphylococcus aureus• Oxacillin – Good oral availability• Cloxacillin• Dicloxacillin13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 26
  27. Broad spectrum – penicillinase (= β- lactamase) sensitive (Also referred to as Aminopenicillins)• Ampicillin – Semisynthetic – Good oral availability – Active against gram-pos and gram-neg bacteria – Active against enterobacteria• Amoxicillin – Excellent oral availability13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 27
  28. Extended spectrum – penicillinase (= β-lactamase) sensitive (Also called Carboxypenicillins) • Carbenicillin – Semisynthetic – Poor oral availability – Active against gram-pos and gram-neg bacteria – Active against Pseudomonas aeruginosa, Klebsiella • Ticarcillin • Mezlocillin • Pipercillin13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 28
  29. Penicillins13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 29 Figure 20.6
  30. CephalosporinesDerived from Cephalosporium sp. (same antibiotic mechanism as penicillins)Cross-allergies with penicillins are commonSome CSs antagonize Vitamin K => leads to bleedingSome CSs block alcohol oxidation => disulfiram effect ( read a bit)Classified into generations:• 1-4• Increasing activity against gram-negative bacterial and anaerobes• Increasing resistance to destruction by beta-lactamases• Increasing ability to reach cerebrospinal fluid13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 30
  31. Cephalosporins• The first cephalosporins - first generation while later, more extended spectrum cephalosporins were classified as second generation cephalosporins.• Each newer generation has significantly greater gram-negative antimicrobial properties than the preceding generation,• Most cases with decreased activity against gram-positive organisms.• Fourth generation cephalosporins, however, have true broad spectrum activity.13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 31
  32. 13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 32
  33. Cephalosporin structure • Base molecule is 7- aminocephalosporanic acid produced by a Sardinian sewer mold • R groups determine spectrum of activity and pharmacological properties • Mechanism of action/resistance and class pharmacology essentially the same as penicillins13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 33
  34. Will consider: • Examples of each generation • Effectiveness • Absorption/Excretion • Distribution • Therapeutic uses • Metabolism Cefaclor structure – Member of The 2nd generation cephalosporins13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 34
  35. First Generation Cephalosporins • Cefazolin, cephalexin, cephadro xil • Excellent against susceptible staph and strep • Modest activity against G -ve • Cefazolin given parentally, others orally • More than half of the drug is bound to plasma proteins • Excreted by kidneys unmetabolized • Good for staph and strep skin and soft tissue infections13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 35
  36. Second Generation Cephalosporins• Include; – Cefaclor, – cefuroxime, – cefprozil• Modest activity against G+, increased activity against G-, works against anaerobes• Cefaclor and cefprozil given orally• Absorption and excretion same as first generation.• Good for treating respiratory tract infections, intra-abdominal infections, pelvic inflammatory disease, diabetic foot ulcers13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 36
  37. Third Generation Cephalosporins• Ceftaxime, ceftriaxzone, cefoperazon e, cefpodoxime• Broad spectrum killers• Drugs of choice for serious infections• No effect against Listeria and beta- lactamase producing pneumococci• Cefpodoxime given orally, others parentally• Most excreted by kidney• Therapeutic uses – Bacterial meningitis (2 exceptions) – Lyme disease – Life-threatening G -ve sepsis (infection) 13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 37
  38. Fourth Generation Cephalosporin – e.g.Cefepime – Same antimicrobial spectrum as third generation but resists more beta-lactamases – Given parentally, excellent penetration into CSF – Good for nosocomial infections13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 38
  39. Toxicity/Contraindications of Cephalosporins • Hypersensitivity reactions (uncommon) essentially same as for penicillins • Cross-reaction between 2 classes13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 39
  40. 13/02/2013 GKM/BIO319:Antibiotics/Sem02/2013 40

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