Chemotherapeutic Agents 

Antibiotics



Synthetic Drugs

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History 

Ancient remedies

– –

________ in egyptian times Quinine



Ehrlich

–

Salvarsan



Domagk

–

Dyes led to discovery of sulfa drugs



Fleming

–

________________ mold

2

Properties of Antimicrobial Agents 

Selective Toxicity

3

Spectrum of Activity 

Narrow



Broad

4

Drug Mechanisms of Action 

Inhibition of Cell Wall Synthesis

–

Bacterial peptidoglycan

–

Bacterial mycolic acid

–

Fungal β-glucans



Disruption of Cell Membrane Function

–

Bacterial membrane proteins - polymyxins

–

Fungal ergosterol

5

Drug Mechanisms of Action 

Inhibition of Protein Synthesis

–

70S vs 80S protein synthesis (bacteria)



Inhibition of Nucleic Acid Synthesis

–

Unique bacterial or viral enzymes may be affected



Antimetabolites

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Essential biochemical pathways are blocked, mostly bacteria, e.g. Folate synthesis inhibition by sulfa drugs

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Side Effects 

Toxicity

– –

Accumulation in kidneys Liver metabolism



Allergy



Disruption of Microflora

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Resistance to Drugs 

Chromosomal mutations



Plasmid borne resistance genes

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Mechanisms of Drug Resistance 

Mutations in Target molecules

–

Ribosome alterations



Alterations in membrane permeability

–

Transport pumps exclude drugs



Enzyme development

–

Penicillinases ( β lactamase)

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Mechanisms of Drug Resistance 

Enzyme Activity Changes

–

PABA binding much greater than sulfa drug binding



Alterations in Anabolic Pathways

–

Uptake of folic acid rather than synthesis

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Generations of Drugs 

First/Second/Third Line Drugs

–

Used as evolving resistances limit the usefulness of original drugs



Cross Resistance

–

Similar drugs are all broken down by the resistant microbe, e.g. β lactamase effects

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Limiting Drug Resistance 

Effective Drug Concentrations



Simultaneous Drug Administration

• •

Synergism Antagonism



Restricting Drug Prescriptions

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Determining Microbial Sensitivities 

Disk Diffusion Method



Dilution Method

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Ideal Antimicrobial Attributes 

Solubility



Selective toxicity



Stable toxicity level



Allergenicity



Tissue stability



Resistance Acquisition



Shelf Life



Cost

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Antibacterials — Cell Wall Target 

Penicillins

–

Natural

–

Semisynthetic

– –

Many Gram +ve’s but Staphylococcus is mostly resistant Safe, but allergies in 1 5% of adults

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Antibacterials — Cell Wall Target 

Cephalosporins

– –

Work similarly to penicillins Safe but more expensive



Carbapenems

– – –

Work like penicillins, more stable Broader spectrum Still effective against Staphylococcus

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Antibacterials — Cell Membrane Target 

Polymyxins

– – –

Topical use only Injure bacterial plasma membrane Used for Pseudomonas dermatitis

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Antibacterials — Protein Synthesis Inhibition    

Aminoglycosides (*mycin)

–

Streptomycin original

• •

Toxicity, deafness Chromosomal mutation causing resistance Tetracyclines (Aureomycin)

– – –

Soluble Good for obligate intracellulars Cause tooth discoloration in children / fetal bone malformations Chloramphenicol

–

Tocicity makes it a drug of last choice in U.S.A.

Macrolides (Erythromycin)

–

Legionnaire’s disease

– –

Bacteriostatic, may be used with other drugs Low toxicity

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Antibacterials — Nucleic Acid Synthesis Inhibition 

Rifampin

– – –

Blocks RNA transcription Red colored, v. soluble Used against M. tuberculosis, N.

meningitidis

–

Many negative interactions with other meds.



Quinolones

– –

Inhibit DNA gyrase Used in traveller’s diarrhea, anthrax

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Antibacterials — Antimetabolites    

Sulfonamides

–

Block folate synthesis Isoniazid

–

Interferes with vitamin B conversions Ethambutol

–

Similar to Isoniazid, often used together Nitrofurans

–

Interfere with KREbs cycle/ETC

– –

Used in UTIs Veterinary topical agent

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Antifungals   

Imidazoles (Clotrimazole)

– – – –

Disrupt ergosterol synthesis Some cross-reactivity with cholesterols Mostly for cutaneous and superficial conditions Ketoconazole – safe for oral administration Polyenes (Amphotericin B)

– –

Ergosterol targeted Systemic infections only, severe side effects Griseofulvin

– –

Impairs mitotic spindle formation Oral admin, for cutaneous and superficial mycoses

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Antifungals 

Flucytosine

–

Nucleoside analog



Tolnaftate/ Terbinafine (Lamisil)

–

Topicals, unclear mech. of action

–

Superficial and cutaneous mycoses

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Antivirals 

Nucleotide analogs

– – –

Ribavirin anti-influenza, anti-herpes Zidovudine (AZT) anti-HIV Acyclovir anti-herpes

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Antivirals 

Amantidine/Rimantidine

– –

Prevents Influenza A virus penetration Ataxia/insomnia in many elderly



Interferons

–

Promote release of antiviral proteins in uninfected cells



Immunoenhancers

–

T lymphocyte stimulators

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Antiprotozoan Drugs 

Quinine/derivatives

–

Malaria



Metronidazole

–

Trichomonas/Giardia



Pyrimethamine

–

Toxoplasmosis



Suramin

–

Trypanosoma

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Antihelminthic Drugs   

Niclosamide

– –

Tapeworms Affect CHO synthesis in worms Mebendazole

– –

Roundworms Blocks glucose uptake Piperazine

– – –

Neurotoxin Pinworms and Ascaris Can cause convulsions in children

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