Dreams of a “Magic Bullet” Birth of Chemotherapy Presentation was developed by Hugh Fackrell Dreams of a “Magic Bullet”
Presentation Outline History “Sulfas” Ideal properties Sources 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 1935, Jacques and Therese Trefoncel discovered that the active compound in Prontosil was Sulfanilamide sulfanilamide “ Sulfas”
Sulfa Drugs
Sulfa vs PABA Sulfanilamide NH2 NH2SO2 PABA NH2 HOOC
Effectiveness of Sulfas Organism must synthesis folic acid eg E coli no effect if folic acid is required eg man and many microbes BACTERIOSTATIC
Structure of Sulfa Drugs Sulfanilamide Sulfisoxazole Prontosil
Folic Acid Metabolism PABA + pteridine Dihydrofolic Acid Pteridine synthetase Dihydropteroic acid [GTP] Sulfonamide Dihydrofolic Acid Dihydrofolate Synthetase L- Glutamine Tetrahydrofolic Acid Dihydrofolate synthetase 2 NADPH 2 NADP+ Trimethoprim Thymidine DNA Purines DNA, RNA Methionine tRNa, Proteins
Folic Acid Inhibition PABA + pteridine Dihydrofolic Acid Sulfonamide Dihydropteroic acid Dihydrofolic Acid Trimethoprim Tetrahydrofolic Acid Thymidine DNA Purines DNA, RNA Methionine tRNa, Proteins
Antibiotic Synergism Sulfisoxazole Trimethoprim
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 1938, Howard Florey and Ernst Chain antibacterial activity in Penicillium mold (called it Penicillin) 1938, Howard Florey and Ernst Chain developed Penicillin as an effective antibiotic
Inhibition of Staphylococcus by Penicillium Staphylococcus Colony Inhibition Penicillium mould
Penicillin prevents Assembly of Bacterial Cell Walls
Penicillium Growing in Broth
Mass Production Used Many Flasks
Penicillium in Vats
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 Bacillus bacitracin, polymyxin, tyrothricin, colimycin, gramicidin Streptomycetes Aminoglycosides, chloramphenicol, erythromycin, tetracylcine, nystatin...