CHEMOTHERAPYCHEMOTHERAPY

QUININEQUININE

• Used by South Used by South American natives to American natives to treat malariatreat malaria

• Bark extract from the Bark extract from the cinchona treecinchona tree

Paul Ehrlich (Germany)Paul Ehrlich (Germany)• Dyes researchDyes research• In the 1920’s dyes were studied In the 1920’s dyes were studied

in the hope to find useful drugsin the hope to find useful drugs• ““Magic bulletMagic bullet””

–Selective toxicitySelective toxicity–Salvarsan (syphilis)Salvarsan (syphilis)

SULFONAMIDESSULFONAMIDES–SulfanilamideSulfanilamide

•StreptococcusStreptococcus infections infections –Prontosil (reddish dye)Prontosil (reddish dye)–The valuable portion of the The valuable portion of the

Prontosil dye was extracted & Prontosil dye was extracted & the sulfonamides were bornthe sulfonamides were born•Inefective in cultures Inefective in cultures

SulfonamidesSulfonamides•They are anti-metabolites

•They interfere with the folic acid pathway

•Folic acid has a functions in the synthesis of purine and pyrimidine

Alexander Fleming (1929)

Penicillium notatum

British Journal of ExperimentalBritish Journal of Experimental Pathology, Vol. 10, 1929Pathology, Vol. 10, 1929

PENICILLINPENICILLIN• 1940 first clinical trials1940 first clinical trials• Still one of the best antibioticsStill one of the best antibiotics• 11stst generation penicillins include generation penicillins include

penicillin G and penicillin V, penicillin G and penicillin V, which are narrow spectrum and which are narrow spectrum and readily inactivated by readily inactivated by penicillinasepenicillinase

STREPTOMYCINSTREPTOMYCIN

• Discovered in the 1940s’Discovered in the 1940s’• Streptomyces griseus (is an Streptomyces griseus (is an

ActinomyceteActinomycete))• Effective against Effective against

Mycobacterium tuberculosisMycobacterium tuberculosis

ANTIBIOSISANTIBIOSIS• Inhibition of growth of Inhibition of growth of

one microorganism by one microorganism by anotheranother

ANTIBIOTICANTIBIOTIC

• A A microbialmicrobial product or its product or its derivative that kills derivative that kills susceptible susceptible microorganisms, or microorganisms, or inhibits their growth inhibits their growth

ANTIBIOTIC-PRODUCING ANTIBIOTIC-PRODUCING ORGANISMSORGANISMS

• BacillusBacillus spp. spp.• Actinomycetes (>50%)Actinomycetes (>50%)

–StreptomycesStreptomyces spp. spp.• FungiFungi

–PenicilliumPenicillium spp. spp.

ACTINOMYCETESACTINOMYCETES

aerobic G+ aerobic G+ bacteria that bacteria that formformbranching branching filamentsfilaments

ACTINOMYCETES ACTINOMYCETES ((cont.cont.))

• StreptomycesStreptomyces spp. spp.–Amphotericin Amphotericin –Chloramphenicol Chloramphenicol (Chloramphenicol is an (Chloramphenicol is an

antibiotic reserved for serious infections especially antibiotic reserved for serious infections especially Hemophilus Hemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitis.influenzae, Streptococcus pneumoniae, and Neisseria meningitis. It is used only when less potentially hazardous therapeutic agents It is used only when less potentially hazardous therapeutic agents are inaffective)are inaffective)

–TetracyclineTetracycline–ErythromycinErythromycin

ACTINOMYCETES (ACTINOMYCETES (cont.cont.))• StreptomycesStreptomyces spp. spp.

–NeomycinNeomycin–NystatinNystatin–StreptomycinStreptomycin–Gentamicin Gentamicin ((MicromonosporaMicromonospora))

NeomycinNeomycin

BacillusBacillus spp. spp.

• BacitracinBacitracin• PolymixinPolymixin

• PenicillinPenicillin• GriseofulvinGriseofulvin• CephalothinCephalothin

FUNGIFUNGI

SPECTRUM OF SPECTRUM OF ANTIMICROBIAL ANTIMICROBIAL

ACTIVITYACTIVITY

• Range of microbial types Range of microbial types affected by the drugaffected by the drug

BROAD SPECTRUMBROAD SPECTRUM• Affects several types of Affects several types of

bacteriabacteria–TetracyclineTetracycline

•Gram + and G- Gram + and G- •Chlamydias and Chlamydias and RickettsiasRickettsias

NARROW SPECTRUMNARROW SPECTRUM• Affects one type of Affects one type of

bacteriabacteria–PenicillinPenicillin

•Gram + primarily but Gram + primarily but some G-some G-

Spectrum of antibiotic Spectrum of antibiotic activityactivity

Mycobacteria Gram negative Gram positive

PenicillinStreptomycin

Tetracycline

ACTION OF ACTION OF ANTIBIOTICSANTIBIOTICS

• BactericidalBactericidal–Kills organismsKills organisms

• BacteriostaticBacteriostatic–Inhibits microorganisms Inhibits microorganisms growthgrowth

INHIBITION OF CELL INHIBITION OF CELL WALL SYNTHESISWALL SYNTHESIS

• Actively growing cells (log Actively growing cells (log phase MO)phase MO)–PenicillinPenicillin–CephalosporinCephalosporin–BacitracinBacitracin–VancomycinVancomycin

Peptidoglycan

Peptidoglycan/vancomycin complex

INHIBITION OF INHIBITION OF PROTEIN SYNTHESISPROTEIN SYNTHESIS

• Eucaryotes 80S ribosomesEucaryotes 80S ribosomes• Procaryotes 70S ribosomesProcaryotes 70S ribosomes• Mitochondria 70S ribosomes Mitochondria 70S ribosomes

(toxicity)(toxicity)• Usually broad spectrumUsually broad spectrum

INHIBITION OF PROTEIN INHIBITION OF PROTEIN SYNTHESIS (SYNTHESIS (cont.cont.))

• ChloranphenicolChloranphenicol• ErythromycinErythromycin• StreptomycinStreptomycin• TetracyclinesTetracyclines

INJURY OF PLASMA INJURY OF PLASMA MEMBRANEMEMBRANE

• Permeability changesPermeability changes–Polymyxin BPolymyxin B

•Attaches to phospholipidsAttaches to phospholipids• Nystatin, amphotericin BNystatin, amphotericin B

–Attach to sterols (ergosterol)Attach to sterols (ergosterol)

INHIBITION OF NUCLEIC INHIBITION OF NUCLEIC ACID REPLICATIONACID REPLICATION

• Inhibition of bacterial DNA Inhibition of bacterial DNA gyrasegyrase–Quinolones Quinolones (brought into the cell via porins)(brought into the cell via porins)

• Inhibition of RNA polymerase Inhibition of RNA polymerase (involved in transcription(involved in transcription DNA to mRNA) DNA to mRNA)

–RifampinRifampin

INHIBITION OF INHIBITION OF SYNTHESIS OF ESSENTIAL SYNTHESIS OF ESSENTIAL

METABOLITESMETABOLITES

• Sulfanilamide inhibits the Sulfanilamide inhibits the synthesis of folic acid by synthesis of folic acid by competitive inhibitioncompetitive inhibition

• Remember folic acid is Remember folic acid is utilized in the formation of utilized in the formation of purines/pyrimidinespurines/pyrimidines

PyrimidinesPyrimidines

PurinesPurines

PENICILLINSPENICILLINS• A common A common lactam ringlactam ring• Over 50 related drugs Over 50 related drugs

–Chemical side chains Chemical side chains attached to the attached to the lactam lactam ring ring

lactam ring lactam ring

Addition of different chemical groups

NATURAL NATURAL PENICILLINSPENICILLINS

• Penicillin G (parenteral)Penicillin G (parenteral)• Penicillin V (oral)Penicillin V (oral)• Narrow spectrumNarrow spectrum• Susceptible to Susceptible to

penicillinasepenicillinase

PenicillinPenicillin

Penicillin G is available in 4 salt forms----sodium, potassium, procaine and benzathine

These are normally administered parentally, either IV or IM, since penicillin G loses much activity in gastric juices

Procaine and benzathine penicillins are the longer-acting forms, and must be given via the IM route only

Penicillin V is available only in the oral form

PENICILLINASEPENICILLINASE

• Bacterial enzyme that Bacterial enzyme that cleaves the cleaves the lactam ring of lactam ring of the penicillin moleculethe penicillin molecule

• Often in Often in StaphylococcusStaphylococcus spp. spp.• Also known asAlso known as lactamaseslactamases

PenicillinPenicillin

To increase the resistance to penicillinase, some penicillins are combined with other agents, such as clavulanic acid or sulbactam

Amoxicillin + clavulanic acid = Augmentin

Ampicillin + sulbactam = Unasyn

SEMISYNTHETIC SEMISYNTHETIC PENICILLINSPENICILLINS

• The The lactam ring is lactam ring is synthesized by synthesized by Penicillium notatum Penicillium notatum and and side chains added later side chains added later chemicallychemically

PenicillinPenicillinPenicillins are effective against the G+ MO primarily and some G- MO (E.coli;Haemophilus influenzae and Salmonella)

They are commonly used to treat sinusitis, pharyngitis and otitis media

They are administered for prophylactic treatment bacterial endocarditis, rheumatic fever and diphtheria

Penicillin G is used in the treatment of pregnant women colonized with GBS

SEMISYNTHETIC SEMISYNTHETIC PENICILLINS (PENICILLINS (cont.cont.))

• Broader spectrumBroader spectrum• Affected by Affected by lactamaseslactamases• Clavulanic acid inhibits Clavulanic acid inhibits lactamaseslactamases

CEPHALOSPORINS CEPHALOSPORINS AND CARBAPENEMSAND CARBAPENEMS

• Similar to penicillinsSimilar to penicillins• Broader spectrumBroader spectrum• Resistant to Resistant to lactamaseslactamases

ANTIVIRAL DRUGSANTIVIRAL DRUGS

• Prevent viral cell entry or Prevent viral cell entry or uncoatinguncoating

• Interfere with nucleic acid Interfere with nucleic acid synthesissynthesis

ANTIVIRAL DRUGS (ANTIVIRAL DRUGS (cont.cont.))• AmantadineAmantadine

–Limited use in Influenza Limited use in Influenza preventionprevention

• RivavirinRivavirin–Viral pneumonia in infantsViral pneumonia in infants

ANTIVIRAL DRUGS ANTIVIRAL DRUGS ((cont.cont.))

• Acyclovir and Acyclovir and GanciclovirGanciclovir–Herpes infectionsHerpes infections

• Zidovudine (AZT)Zidovudine (AZT)–HIVHIV

EVALUATION OF EVALUATION OF ANTIMICROBIAL ANTIMICROBIAL

ACTIVITYACTIVITY

• Disk-diffusion methodDisk-diffusion method• Broth-dilution methodBroth-dilution method

DISK-DIFFUSION DISK-DIFFUSION METHODMETHOD

• Not very accurateNot very accurate• Cannot differentiate Cannot differentiate

between bactericidal and between bactericidal and bacteriostatic drugsbacteriostatic drugs

• Simple and inexpensiveSimple and inexpensive

DISK-DIFFUSION METHODDISK-DIFFUSION METHOD

DRUG RESISTANCEDRUG RESISTANCE• Transferred mostly by Transferred mostly by

plasmidsplasmids• Mechanisms:Mechanisms:

–Inactivation of the drugInactivation of the drug–Prevention of penetrationPrevention of penetration–Alteration of target sitesAlteration of target sites

DRUG COMBINATIONDRUG COMBINATION• SynergismSynergism

–Greater than the effect of Greater than the effect of either given aloneeither given alone

• AntagonismAntagonism–Less effective than one of Less effective than one of the drugs alonethe drugs alone