Ehrlich’s Magic Bullets
Paul Ehrlich(1854 –1915), Nobel Prize for Medicine in 1908, Salvarsan and 606Dr Paul Ehrlich &
Dr Hata Sahachiro
Selective toxicity: A drug that kills harmful microbes without damaging the host
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
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
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
Mechanism of Action
PABA Folic Acid
Dihydrofolic Acid
Tetrahydrofolic AcidFolinic
AcidDNA synthesis
DIHYDROPTEROATE SYNTHASE
Folic Acid reductase
Dihydrofolic acid reductase
FORMYL GROUP TRANSFER
Sulfonamides
Trimethoprim
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
• 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
• Penicilinase-resistant penicillins• Carbapenems: very broad spectrum• Monobactam: Gram negative
• Extended-spectrum penicillins• Penicillins + -lactamase inhibitors
Semisynthetic Penicillins
• 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
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
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
• Inhibit assembly– Indinavir (HIV)
• Inhibit attachment– Zanamivir (Influenza)
• Inhibit uncoating– Amantadine (Influenza)
Antiviral DrugsEnzyme Inhibitors
• Interferons prevent spread of viruses to new cells (Viral hepatitis)
• Natural products of the immune system in viral infections
Antiviral DrugsEnzyme 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 (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).