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Birth of ChemotherapyBirth of Chemotherapy

Dreams of a “Magic Bullet”Dreams of a “Magic Bullet”

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Presentation OutlinePresentation Outline HistoryHistory

– SalvorsanSalvorsan– SulfaSulfa– PenicillinPenicillin

““Sulfas”Sulfas”– AntimetabolitesAntimetabolites– antibiotic synergismantibiotic synergism

Ideal propertiesIdeal properties SourcesSources

Filename: Chemotheraphy.ppt

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SemmelweissSemmelweiss

Jena, AustriaJena, Austria ““Laying in” hospitalsLaying in” hospitals Peurperal feverPeurperal fever Cleanliness in surgeryCleanliness in surgery

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Joseph ListerJoseph Lister

Developed antiseptic surgery

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Early AntibioticsEarly Antibiotics

Salvarsan 606- failureSalvarsan 606- failure Prontosil- developed by careful Prontosil- developed by careful

researchresearch Penicillin- discovered accidentlyPenicillin- discovered accidently

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Paul EhrlichPaul Ehrlich

Noble PrizeNoble Prize ChemotherapyChemotherapy Theory of Theory of

immunityimmunity

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Salvarsan 606Salvarsan 606

Paul EhrlichPaul Ehrlich– early 1900’searly 1900’s– syphilissyphilis– arsenic + organic compoundarsenic + organic compound

Aniline dyes - Aniline dyes -

– wasn't able to find the "magic bullet”wasn't able to find the "magic bullet”

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ProntosilProntosil

1930's, Gerhard Domagk1930's, Gerhard Domagk– ProntosilProntosil

1935, Jacques and Therese 1935, Jacques and Therese TrefoncelTrefoncel– discovered that the active compound discovered that the active compound

in Prontosil was Sulfanilamidein Prontosil was Sulfanilamide sulfanilamide “ Sulfas”sulfanilamide “ Sulfas”

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Sulfa DrugsSulfa Drugs

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Sulfa vs PABASulfa vs PABA

PABAPABA

NHNH22HOOCHOOC

SulfanilamidSulfanilamidee

NHNH22NHNH22SOSO22

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Effectiveness of SulfasEffectiveness of Sulfas

Organism must synthesis folic acidOrganism must synthesis folic acid– eg eg E coliE coli

no effect if folic acid is requiredno effect if folic acid is required– eg man and many microbeseg man and many microbes

BACTERIOSTATIC BACTERIOSTATIC

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Structure of Sulfa DrugsStructure of Sulfa Drugs

ProntosilProntosil

SulfisoxazoleSulfisoxazole

SulfanilamideSulfanilamide

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Folic Acid MetabolismFolic Acid MetabolismPABA + pteridinePABA + pteridine

ThymidineThymidine

DNADNA

PurinesPurines

DNA, RNADNA, RNA

MethionineMethionine

tRNa, tRNa, ProteinsProteins

Pteridine Pteridine synthetasesynthetase

Dihydropteroic acidDihydropteroic acid

[GTP][GTP]

Dihydrofolic AcidDihydrofolic Acid

Dihydrofolate Dihydrofolate SynthetaseSynthetase

L- GlutamineL- Glutamine

Tetrahydrofolic AcidTetrahydrofolic Acid

DihydrofolatDihydrofolate e synthetasesynthetase

2 NADPH2 NADPH

2 2 NADP+NADP+

SulfonamidSulfonamidee

TrimethopriTrimethoprimm

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ThymidineThymidine

DNADNA

PurinesPurines

DNA, RNADNA, RNA

MethionineMethionine

tRNa, tRNa, ProteinsProteins

Folic Acid InhibitionFolic Acid InhibitionPABA + pteridinePABA + pteridine

Dihydropteroic acidDihydropteroic acid

Dihydrofolic AcidDihydrofolic Acid

Tetrahydrofolic AcidTetrahydrofolic Acid

SulfonamidSulfonamidee

TrimethopriTrimethoprimm

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Antibiotic SynergismAntibiotic SynergismSulfisoxazoleSulfisoxazole

TrimethopriTrimethoprimm

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Antibiotic SynergismAntibiotic Synergism

Sulfonamide + trimethoprimSulfonamide + trimethoprim Effective dosage 10% of two Effective dosage 10% of two

separatelyseparately Broader spectrum of actionBroader spectrum of action Reduce emergence of resistant Reduce emergence of resistant

strainsstrains

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Alexander FlemmingAlexander Flemming

Discovered penicillinDiscovered penicillin

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PenicillinPenicillin

1928, Alexander Fleming1928, Alexander Fleming– antibacterial activity in Penicillium antibacterial activity in Penicillium

mold (called it Penicillin)mold (called it Penicillin) 1938, Howard Florey and Ernst 1938, Howard Florey and Ernst

ChainChain– developed Penicillin as an effective developed Penicillin as an effective

antibioticantibiotic

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Inhibition of Inhibition of StaphylococcusStaphylococcus by by

PenicilliumPenicillium

Staphylococcus Colony

Penicillium mould

Inhibition

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Penicillin prevents Penicillin prevents Assembly of Bacterial Cell Assembly of Bacterial Cell

WallsWalls

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PenicilliumPenicillium Growing in Growing in BrothBroth

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Mass Production Used Many Mass Production Used Many FlasksFlasks

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Penicillium in VatsPenicillium in Vats

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Antimicrobial TherapyAntimicrobial Therapy AntimicrobicsAntimicrobics

– substances produced by microbes substances produced by microbes that inhibit other microbesthat inhibit other microbes

Semi-synthetic antibioticsSemi-synthetic antibiotics– naturally produced but alterednaturally produced but altered

Synthetic antibioticsSynthetic antibiotics::– derived from chemicalsderived from chemicals

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Ideal Properties of an Ideal Properties of an AntibioticAntibiotic

Low toxicity for patientLow toxicity for patient– kills the invading microorganism without kills the invading microorganism without

damaging the hostdamaging the host– no adverse side reactionsno adverse side reactions– non allergenicnon allergenic

High toxicity for microbeHigh toxicity for microbe– bactericidal not bacteriostaticbactericidal not bacteriostatic– broad spectrumbroad spectrum

Low risk of other infectionsLow risk of other infections

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More CharacteristicsMore Characteristics

drug can be administered orally or drug can be administered orally or parenterally (by injection)parenterally (by injection)– Soluble in tissue fluidsSoluble in tissue fluids– absorbed by and dissolved in tissues absorbed by and dissolved in tissues

or body fluidsor body fluids levels of active drug sustained long levels of active drug sustained long

enough to kill the invading agentenough to kill the invading agent Long “Shelf” lifeLong “Shelf” life

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Still More CharacteristicsStill More Characteristics

Low probability of resistanceLow probability of resistance Microbial drug resistance develops Microbial drug resistance develops

slowlyslowly microbicidal rather than microbistaticmicrobicidal rather than microbistatic Not inactivated by organic materialNot inactivated by organic material Assists the host in eliminating the Assists the host in eliminating the

infecting microbeinfecting microbe Not a powerful allergenNot a powerful allergen

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Sources of AntibioticsSources of AntibioticsMost spore-forming microorganismsMost spore-forming microorganisms FungiFungi

– PenicilliumPenicillium penicillin, penicillin, – CephalosporiumCephalosporium griseofulvin griseofulvin

BacteriaBacteria– BacillusBacillus bacitracin, polymyxin, tyrothricin, bacitracin, polymyxin, tyrothricin,

colimycin, gramicidincolimycin, gramicidin– StreptomycetesStreptomycetes Aminoglycosides, Aminoglycosides,

chloramphenicol, erythromycin, tetracylcine, chloramphenicol, erythromycin, tetracylcine, nystatin...nystatin...