Chemical Medicine Antimicrobial Drugs, Sulfa Drugs

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

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

Sulfa Drugs, History/Discovery Discovered by Gerhard Domagk ( ), 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 zes/medicine/laureates/1939/ domagk.jpg

Sulfa Drugs in World War II The discovery of Sulfa nilamide greatly affect ed the mortality rate d uring World War II. American soldiers were taught to immediately sprinkle sulfa powder on any open wound to prevent infection.

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 PABA Folic Acid Dihydrofolic Acid Tetrahydrofolic Acid Folinic Acid DNA synthesis DIHYDROPTEROATE SYNTHASE Folic Acid reductase Dihydrofolic acid reductase FORMYL GROUP TRANSFER Sulfonamides Trimethoprim

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

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

Prokaryotic Cell Walls

Penicillins

Penicillinase (  Lactamase)

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

Cephalosporins –2 nd, 3 rd, and 4 th 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

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) Inhibitors of Protein Synthesis

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

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

–Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum Competitive Inhibitors

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

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 Antiviral Drugs Enzyme Inhibitors

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

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

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 The Future of Chemotherapeutic Agents

References Gray, J., Therapeutic Choices, Canadian Pharmacists Association, 2007 (1112, 1448) Steinert, D. History of WWII Medicine, World War II Combat Medic ( Ophardt, C. “Antibacterial Agents, Sulfa Drugs”, Virtual Chembook ( Dharmananda, S., Differentiating Sulfur Compounds: Sulfa Drugs, Glucosamine Sulfate, Sulfur, and Sulfiting Agents. Institute for Traditional Medicine. (