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Chemical Medicine

Chemical Medicine. Antimicrobial Drugs, Sulfa Drugs. Ehrlich’s Magic Bullets . Selective toxicity : A drug that kills harmful microbes without damaging the host. Paul Ehrlich(1854 –1915), Nobel Prize for Medicine in 1908, Salvarsan and 606. Dr Paul Ehrlich & Dr Hata Sahachiro.

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Chemical Medicine

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  1. Chemical Medicine Antimicrobial Drugs, Sulfa Drugs

  2. Ehrlich’s Magic Bullets Selective toxicity: A drug that kills harmful microbes without damaging the host PaulEhrlich(1854 –1915), Nobel Prize for Medicine in1908, Salvarsan and 606 Dr Paul Ehrlich & Dr Hata Sahachiro

  3. Fleming and Penicillin Alexander Fleming(1881 –1955), Nobel Prize in Physiology or Medicine (1945)

  4. Sulfa Drugs, History/Discovery • Discovered by Gerhard Domagk (1895-1964), a German biochemist • In 1932, tested a dye, Prontosil • Although it had no antibacterial properties, a slight change in its chemical make-up resulted in anti-bacterial activity against streptococci in mice • Derivatives based on the Prontosil sulfonamide group were developed, resulting in so-called sulfa drugs • Sulfa drugs revolutionized medicine and saved many thousands of lives http://nobelprize.org/nobel_prizes/medicine/laureates/1939/domagk.jpg

  5. Sulfa Drugs in World War II • The discovery of Sulfanilamide greatly affected the mortality rate during World War II. • American soldiers were taught to immediately sprinkle sulfa powder on any open wound to prevent infection. http://home.att.net

  6. Sulfanilamide Grandparent of sulfonamide family of drugs first used in 1936 Sulfanilamide and its derivatives were said to have “dethroned the captain of the men of death” Prontosil 4-[(2,4-diaminophenyl)azo]benzenesulfonamide Sulfanilamide 4-aminobenzenesulfonamide

  7. Chemical structures

  8. FOLIC ACID

  9. Mechanism of Action DIHYDROPTEROATE SYNTHASE Folic Acid reductase Dihydrofolic Acid PABA Folic Acid Trimethoprim Dihydrofolic acid reductase Sulfonamides FORMYL GROUP TRANSFER Tetrahydrofolic Acid DNA synthesis Folinic Acid

  10. Microbial Sources of Antibiotics

  11. Antibiotic Spectrum of Activity • No antibiotic is effective against all microbes

  12. Mechanisms of Antimicrobial Action • Bacteria have their own enzymes for • Cell wall formation • Protein synthesis • DNA replication • RNA synthesis • Synthesis of essential metabolites • Viruses use host enzymes inside host cells • Fungi and protozoa have own eukaryotic enzymes • The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have

  13. Modes of Antimicrobial Action

  14. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin (over 50 compounds) • Share 4-sided ring (b lactam ring) • Natural penicillins • Narrow range of action • Susceptible to penicillinase (b lactamase)

  15. Prokaryotic Cell Walls

  16. Penicillins

  17. Penicillinase (b Lactamase)

  18. Semisynthetic Penicillins • Penicilinase-resistant penicillins • Carbapenems: very broad spectrum • Monobactam: Gram negative • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors

  19. Other Inhibitors of Cell Wall Synthesis • Cephalosporins • 2nd, 3rd, and 4th generations more effective against gram-negatives

  20. Other Inhibitors of Cell Wall Synthesis • Polypeptide antibiotics • Bacitracin • Topical application • Against gram-positives • Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus

  21. Other Inhibitors of Cell Wall Synthesis • Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation • Isoniazid (INH) • Ethambutol

  22. Inhibitors of Protein Synthesis • Broad spectrum, toxicity problems • Examples • Chloramphenicol (bone marrow) • Aminoglycosides: Streptomycin, neomycin, gentamycin (hearing, kidneys) • Tetracyclines (Rickettsias & Chlamydia; GI tract) • Macrolides: Erythromycin (gram +, used in children)

  23. Injury to the Plasma Membrane • Polymyxin B (Gram negatives) • Topical • Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation

  24. Inhibitors of Nucleic Acid Synthesis • Rifamycin • Inhibits RNA synthesis • Antituberculosis • Quinolones and fluoroquinolones • Ciprofloxacin • Inhibits DNA gyrase • Urinary tract infections

  25. Competitive Inhibitors • Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum

  26. Antifungal Drugs • Fungi are eukaryotes • Have unique sterols in their cell walls • Pathogenic fungi are often outside the body

  27. Antiviral Drugs • Viruses are composed of nucleic acid, protein capsid, and host membrane containing virus proteins • Viruses live inside host cells and use many host enzymes • Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly

  28. Antiviral DrugsNucleoside and Nucleotide Analogs

  29. Analogs Block DNA Synthesis

  30. Antiviral DrugsEnzyme Inhibitors • Inhibit assembly • Indinavir (HIV) • Inhibit attachment • Zanamivir (Influenza) • Inhibit uncoating • Amantadine (Influenza)

  31. Antiviral DrugsEnzyme Inhibitors • Interferons prevent spread of viruses to new cells (Viral hepatitis) • Natural products of the immune system in viral infections

  32. Antiprotozoan Drugs • Protozoa are eukaryotic cells • Many drugs are experimental and their mode of action is unknown

  33. Antihelminthic Drugs • Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms

  34. Antihelminthic Drugs • Prevent ATP generation (Tapeworms) • Alters membrane permeability (Flatworms) • Neuromuscular block (Intestinal roundworms) • Inhibits nutrient absorption (Intestinal roundworms) • Paralyzes worm (Intestinal roundworms)

  35. The Future of Chemotherapeutic Agents • Antimicrobial peptides • Broad spectrum antibiotics from plants and animals • Squalamine (sharks) • Protegrin (pigs) • Magainin (frogs) • Antisense agents • Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription

  36. References • Gray, J., Therapeutic Choices, Canadian Pharmacists Association, 2007 (1112, 1448) • Steinert, D. History of WWII Medicine, World War II Combat Medic (http://home.att.net/~steinert/wwii.htm) • Ophardt, C. “Antibacterial Agents, Sulfa Drugs”, Virtual Chembook (http://www.elmhurst.edu/~chm/vchembook/653sulfa.html) • Dharmananda, S., Differentiating Sulfur Compounds: Sulfa Drugs, Glucosamine Sulfate, Sulfur, and Sulfiting Agents. Institute for Traditional Medicine. (http://www.itmonline.org/arts/sulfa.html).

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