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Chemical Medicine Antimicrobial Drugs, Sulfa Drugs Ehrlich’s Magic Bullets Selective toxicity: A drug that kills harmful microbes without damaging the host Dr Paul Ehrlich & Dr Hata Sahachiro Paul Ehrlich(1854 –1915), Nobel Prize for Medicine in 1908, Salvarsan and 606 Fleming and Penicillin Alexander Fleming(1881 –1955), Nobel Prize in Physiology or Medicine (1945) Sulfa Drugs, History/Discovery http://nobelprize.org/nobel_ prizes/medicine/laureates/19 39/domagk.jpg • 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 Sulfa Drugs in World War II • The discovery of Sulfa nilamide greatly affect ed 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 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 Chemical structures FOLIC ACID Mechanism of Action DIHYDROPTEROATE SYNTHASE PABA Folic Acid reductase Dihydrofolic Acid Folic Acid Trimethoprim Dihydrofolic acid reductase Sulfonamides DNA synthesis FORMYL GROUP TRANSFER Folinic Acid Tetrahydrofolic Acid Microbial Sources of Antibiotics Antibiotic Spectrum of Activity • No antibiotic is effective against all microbes 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 Modes of Antimicrobial Action 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) Prokaryotic Cell Walls Penicillins Penicillinase (b Lactamase) Semisynthetic Penicillins • Penicilinase-resistant penicillins • Carbapenems: very broad spectrum • Monobactam: Gram negative • Extended-spectrum penicillins • Penicillins + b-lactamase inhibitors Other Inhibitors of Cell Wall Synthesis • Cephalosporins – 2nd, 3rd, and 4th generations more effective against gram-negatives Other Inhibitors of Cell Wall Synthesis • Polypeptide antibiotics – Bacitracin • Topical application • Against gram-positives – Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus Other Inhibitors of Cell Wall Synthesis • Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation – Isoniazid (INH) – Ethambutol 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) Injury to the Plasma Membrane • Polymyxin B (Gram negatives) – Topical – Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation Inhibitors of Nucleic Acid Synthesis • Rifamycin – Inhibits RNA synthesis – Antituberculosis • Quinolones and fluoroquinolones – Ciprofloxacin – Inhibits DNA gyrase – Urinary tract infections Competitive Inhibitors – Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Antifungal Drugs • Fungi are eukaryotes • Have unique sterols in their cell walls • Pathogenic fungi are often outside the body 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 Antiviral Drugs Nucleoside and Nucleotide Analogs Analogs Block DNA Synthesis Antiviral Drugs Enzyme Inhibitors • Inhibit assembly – Indinavir (HIV) • Inhibit attachment – Zanamivir (Influenza) • Inhibit uncoating – Amantadine (Influenza) Antiviral Drugs Enzyme Inhibitors • Interferons prevent spread of viruses to new cells (Viral hepatitis) • Natural products of the immune system in viral infections Antiprotozoan Drugs • Protozoa are eukaryotic cells • Many drugs are experimental and their mode of action is unknown Antihelminthic Drugs • Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms Antihelminthic Drugs • Prevent ATP generation (Tapeworms) • Alters membrane permeability (Flatworms) • Neuromuscular block (Intestinal roundworms) • Inhibits nutrient absorption (Intestinal roundworms) • Paralyzes worm (Intestinal roundworms) 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 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).