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Dreams of a “Magic Bullet”. Birth of Chemotherapy. Presentation Outline. History Salvorsan Sulfa Penicillin “Sulfas” Antimetabolites antibiotic synergism Ideal properties Sources. Filename: Chemotheraphy.ppt. Semmelweiss. Jena, Austria “Laying in” hospitals Peurperal fever
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Dreams of a “Magic Bullet” Birth of Chemotherapy
Presentation Outline • History • Salvorsan • Sulfa • Penicillin • “Sulfas” • Antimetabolites • antibiotic synergism • Ideal properties • Sources Filename: Chemotheraphy.ppt
Semmelweiss • Jena, Austria • “Laying in” hospitals • Peurperal fever • Cleanliness in surgery
Joseph Lister Developed antiseptic surgery
Early Antibiotics • Salvarsan 606- failure • Prontosil- developed by careful research • Penicillin- discovered accidently
Paul Ehrlich • Noble Prize • Chemotherapy • Theory of immunity
Salvarsan 606 • Paul Ehrlich • early 1900’s • syphilis • arsenic + organic compound • Aniline dyes - • wasn't able to find the "magic bullet”
Prontosil • 1930's, Gerhard Domagk • Prontosil • 1935, Jacques and Therese Trefoncel • discovered that the active compound in Prontosil was Sulfanilamide • sulfanilamide “ Sulfas”
NH2SO2 NH2 Sulfanilamide NH2 HOOC PABA Sulfa vs PABA
Effectiveness of Sulfas • Organism must synthesis folic acid • eg E coli • no effect if folic acid is required • eg man and many microbes • BACTERIOSTATIC
Sulfisoxazole Sulfanilamide Prontosil Structure of Sulfa Drugs
Pteridine synthetase [GTP] Dihydropteroic acid Dihydrofolate Synthetase L- Glutamine Dihydrofolic Acid 2 NADPH Dihydrofolate synthetase 2 NADP+ Tetrahydrofolic Acid Thymidine Purines Methionine DNA DNA, RNA tRNa, Proteins Folic Acid Metabolism PABA + pteridine Sulfonamide Trimethoprim
Sulfonamide Trimethoprim Thymidine Purines Methionine DNA DNA, RNA tRNa, Proteins Folic Acid Inhibition PABA + pteridine Dihydropteroic acid Dihydrofolic Acid Tetrahydrofolic Acid
Sulfisoxazole Trimethoprim Antibiotic Synergism
Antibiotic Synergism • Sulfonamide + trimethoprim • Effective dosage 10% of two separately • Broader spectrum of action • Reduce emergence of resistant strains
Alexander Flemming • Discovered penicillin
Penicillin • 1928, Alexander Fleming • antibacterial activity in Penicillium mold (called it Penicillin) • 1938, Howard Florey and Ernst Chain • developed Penicillin as an effective antibiotic
Inhibition Inhibition of Staphylococcus by Penicillium Staphylococcus Colony Penicillium mould
Antimicrobial Therapy • Antimicrobics • substances produced by microbes that inhibit other microbes • Semi-synthetic antibiotics • naturally produced but altered • Synthetic antibiotics: • derived from chemicals
Ideal Properties of an Antibiotic • Low toxicity for patient • kills the invading microorganism without damaging the host • no adverse side reactions • non allergenic • High toxicity for microbe • bactericidal not bacteriostatic • broad spectrum • Low risk of other infections
More Characteristics • drug can be administered orally or parenterally (by injection) • Soluble in tissue fluids • absorbed by and dissolved in tissues or body fluids • levels of active drug sustained long enough to kill the invading agent • Long “Shelf” life
Still More Characteristics • Low probability of resistance • Microbial drug resistance develops slowly • microbicidal rather than microbistatic • Not inactivated by organic material • Assists the host in eliminating the infecting microbe • Not a powerful allergen
Sources of Antibiotics Most spore-forming microorganisms • Fungi • Penicillium penicillin, • Cephalosporium griseofulvin • Bacteria • Bacillusbacitracin, polymyxin, tyrothricin, colimycin, gramicidin • StreptomycetesAminoglycosides, chloramphenicol, erythromycin, tetracylcine, nystatin...