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Antibiotics Lecture 04


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Antibiotics Lecture 04

  1. 1. Bio 319: Antibiotics Lecture Four Topic Inhibitors of Nucleic acid synthesis Inhibitors of synthesis of essential metabolites Introduction to antibiotics resistance Lecturer: Dr. G. Kattam Maiyoh03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 1
  2. 2. Reminder03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 2
  3. 3. The Action of Antimicrobial Drugs03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 3
  4. 4. Inhibitors of Cell Wall Synthesis03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 4
  5. 5. Protein synthesis inhibitors – Aminoglycosides – Tetracyclins - Spectinomycin – Macrolides – Chloramphenicol – Clindamycin03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 5
  6. 6. Inhibitors of Nucleic Acid Synthesis ~Inhibitors of DNA synthesis ~Inhibitors of RNA synthesis03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 6
  7. 7. Inhibitors of RNA Synthesis For this class of antibiotics, selectivity is due to differences between prokaryotic and eukaryotic RNA polymerase i.e. All RNA polymerases are multi-protein complexes, however, the number of proteins that are assembled to form the active enzyme is much larger in eukaryotes; •The basic catalytic core is made up of 12 subunits. •By comparison, bacterial RNAP has 5 subunits.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 7
  8. 8. Rifampin, Rifamycin, Rifampicin, Rifabutin (bactericidal)• Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis.• Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis• Resistance – Common – For example; – Resistance to rifampicin develops quickly during treatment, so monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics. – Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.• Combination therapy - Since resistance is common, rifampin is usually used in combination therapy.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 8
  9. 9. Inhibitors of DNA SynthesisFor this class of antibiotics, selectivity due to differences between prokaryoticand eukaryotic DNA replication enzymesConsider the following:Eukaryotic replication is more complicated. •First, they have multiple ori per chromosome that allow for bidirectional synthesis of the linear chromosome. •They also use several DNA polymerases (I, II, III), and ligase (seals the nicks in the DNA strand), and RNA primer (gives a 3 end for the DNA polymerase to start synthesis).•As for other differences in their synthesis of DNA is their speed,prokaryotes can replicate their chromosome at about 1,000 bp/sec, whileeukaryotes can replicate their chromosomes at about 100 bp/sec.•They also differ in the number of ori, eukaryotes (as it was stated above)has multiple ori, while prokaryotes have only one.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 9
  10. 10. The Quinolones • Current drugs are fluoridated 4-quinolones • Broad coverage (some broader than others) • Targets DNA gyrase (G-) and topoisomerase IV (G+) • Resistance due to efflux and mutations in targets03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 10
  11. 11. Pharmacological attributes of Quinolones • Favorable pharmacological attributes – Orally administered, quickly absorbed, even with a full stomach – Excellent bioavailability in a wide range of tissues and body fluids (including inside cells) • Mostly cleared by the kidneys – Exceptions are pefloxacin and moxifloxacin which are metabolized by liver • Ciprofloxacin, ofloxacin, and pefloxacin are excreted in breast milk “Got Cipro?”03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 11
  12. 12. Therapeutic Uses of Quinolones • Urinary tract infections • Prostatitis • STD’s – Chlamydia – Chancroid - painful sores on the genitalia – Not syphilis or gonorrhea (due to increased resistance)03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 12
  13. 13. Therapeutic Uses of Quinolones • GI and abdominal – Travelers diarrhea – Shigellosis – Typhoid fever • Respiratory tract – New agents for strep. pneumonia03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 13
  14. 14. Therapeutic Uses of Quinolones • Bone, joint, soft tissue – Ideal for chronic osteomylitis - infection of the bone or bone marrow • Resistance developing in S. aureus, P. aeruginosa, and S. marcesens – Good against polymicrobial infections like diabetic foot ulcers03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 14
  15. 15. Therapeutic Uses of Quinolones • Ciprofloxacin for anthrax and tuleremia (rabbit fever, deer fly fever, Oharas fever) • Combined with other drugs, useful for atypical Mycobacterium sp. Pulmonary Anthrax03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 15
  16. 16. Toxicity/Contraindications of Quinolones• Nausea, vomiting, abdominal discomfort (common)• Diarrhea and antibiotic-associated colitis (uncommon to rare)• CNS side effects – Mild headache and dizziness (common to rare) – Hallucinations, delirium, and seizures (rare)• Arthropy in immature animals (common) – Quinolones not given to children unless benefits outweigh the risks• Leukopenia, eosinophila, heart arythmias (rare)delirium - disorder involving incoherent speech, hallucinations, etc., caused by intoxication, fever, etc03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 16
  17. 17. Antimetabolite Antimicrobials03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 17
  18. 18. Inhibitors of Folic Acid Synthesis p-aminobenzoic acid + Pteridine Pteridine• Basis of Selectivity Sulfonamides synthetase• Review of Folic Dihydropteroic acid Acid Metabolism Dihydrofolate synthetase Dihydrofolic acid Dihydrofolate Trimethoprim reductase Tetrahydrofolic acid Thymidine Methionine03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 Purines 18
  19. 19. Sulfonamides, Sulfones (bacteriostatic)• Mode of action - These antimicrobials are analogues of para- aminobenzoic acid and competitively inhibit formation of dihydropteroic acid.• Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.• Resistance - Common• Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 19
  20. 20. Trimethoprim, Methotrexate, Pyrimethamine (bacteriostatic)• Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid.• Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.• Resistance - Common• Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 20
  21. 21. Sulfonamides • Analogues of para-aminobenzoic acid • Broad spectrum • Competitive inhibitors of dihydropteroate synthase – needed for folic acid synthesis Gerhard Domagk gets a Nobel for Medicine, 1939.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 21
  22. 22. Sulfonamides• Mostly absorbed from GI tract• Binds variably to serum albumin• Wide tissue distribution, including transplacentally• Variably inactivated in liver by acetylation and then excreted in urine• Some agents can precipitate in acid urine03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 22
  23. 23. 1. Rapidly Absorbed and Eliminated Sulfonamides • Sulfisoxazole, sulfamethoxazole, sulfadiazine • Bind extensively to plasma proteins • Highly concentrated in urine (cidal) • Sulfamethoxazole combined with trimethoprim (Bactrim) is widely used to treat a variety of infections (esp. UTI)03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 23
  24. 24. 2. Poorly Absorbed Sulfonamides• E.g. Sulfasalazine• Poorly absorbed in GI tract• Used to treat ulcerative colitis and irritable bowel syndrome• Gut flora metabolize drug into 2 compounds, 1 toxic- sulfapyridine, 1 therapeutic (5-aminosalicylate)• Hence is a prodrug – effective after breakdown Ulcerative Colitis 03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 24
  25. 25. Sulfonamides for Topical Use • E.g. 1.Sulfacetamide – Good penetration in eye – Non-irritating • 2. Silver sulfadiazine – Prevention and treatment of burn wound infections Bacterial corneal infection03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 25
  26. 26. Long Acting Sulfonamide • Serum half-life is measured in days rather than minutes or hours • E.g. Sulfadoxine • Combined with pyirethamine to treat malaria Plasmodium vivax03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 26
  27. 27. Therapeutic Uses of Sulfonamides • Urinary tract infections • Nocardiosis -serious infection caused by a fungus-like bacterium that begins in the lungs and can spread to the brain. • Toxoplasmosis - caused by protozoan (avoid using in pregnant women) Nocardia asteroides03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 27
  28. 28. Toxicity/Contraindications of Sulfonamides - UT • Crystallization in acid urine – Common to uncommon depending on drug. – Alkalize urine or increase hydration03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 28
  29. 29. Toxicity/Contraindications of Sulfonamides - blood• Acute hemolytic anemia – Rare to extremely rare – Associated with glucose-6-phosphate dehydrogenase activity in RBC• Agranulocytosis - failure of the bone marrow to make enough white blood cells (neutrophils). (extremely rare)• Aplastic anemia - marrow doesnt make enough new blood cells. (extremely rare)03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 29
  30. 30. Toxicity/Contraindications of Sulfonamides - immune• Hypersensitivity reactions (common to uncommon) – Skin and mucous membrane manifestations (rashes) – Serum sickness - type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum – Focal or diffuse necrosis of the liver (rare)03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 30
  31. 31. Toxic Epidermal Necrolysis (TEN)03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 31
  32. 32. Toxicity/Contraindications of Sulfonamides - miscellaneous • Nausea, anorexia, vomiting (common) • Kernicterus; damage caused by excessive jaundice – Displacement of bilirubin from plasma albumin to brain resulting in encephalopathy(disease of the brain) – Never give sulfa drugs to a pregnant or lactating woman Bilirubin deposits in neonatal • Potentiation of oral coagulants, brain sulfonylurea hypoglycemic drugs, and hydrantoin anticonvulsants03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 32
  33. 33. INJURY TO THE PLASMA MEMBRANE - Brief• All cells are bound by a cell membrane.• And although the membranes of all cells are quite similar, those of bacteria and fungi differ from eukaryotic cells.• These slight differences allow for selective action of some antimicrobial agents.• Certain antibiotics, like polymyxins, act as detergents to dissolve bacterial cell membranes by binding to phospholipids present in the membranes.03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 33
  34. 34. Antibiotic Resistance• A variety of mutations can lead to antibiotic resistance• Mechanisms of antibiotic resistance 1. Enzymatic destruction of drug 2. Prevention of penetration of drug 3. Alteration of drugs target site 4. Rapid ejection of the drug• Resistance genes are often on plasmids or transposons that can be transferred between bacteria. 03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 34
  35. 35. Transmission of drug resistance• Transmission of drug resistance – Bacterial plasmids – Transposons – Bacteriophages03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 35
  36. 36. Resistance to Antibiotics03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 36
  37. 37. Role of “misuse” • Misuse of antibiotics selects for resistance mutants. • Misuse includes; – Using outdated or weakened antibiotics – Using antibiotics for the common cold and other inappropriate conditions – Using antibiotics in animal feed – Failing complete the prescribed regimen – Using someone elses leftover prescription03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 37
  38. 38. Microbe Library American Society for Microbiology www.microbelibrary.org03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 38
  39. 39. Antimicrobial Drug Resistance Mechanisms • Altered permeability – Altered efflux • tetracycline Microbe Library American Society for Microbiology www.microbelibrary.org03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 39
  40. 40. Antimicrobial Drug Resistance Mechanisms • Inactivation – β-lactamase – Chloramphenicol acetyl transferase Microbe Library American Society for Microbiology www.microbelibrary.org03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 40
  41. 41. Antimicrobial Drug Resistance Mechanisms • Altered target site – Penicillin binding proteins (penicillins) – RNA polymerase (rifampin) – 30S ribosome (streptomycin) Microbe Library American Society for Microbiology www.microbelibrary.org03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 41
  42. 42. Antimicrobial Drug Resistance Mechanisms • Replacement of a sensitive pathway – Acquisition of a resistant enzyme (sulfonamides, trimethoprim) 03/21/13 GKM/BIO319:Antibiotics/Sem2/2013 42