PAUL EHRLICH DEVELOPED MODERN

CONCEPT OF CHEMOTHERAPY AND

CHEMOTHERAPEUTIC AGENTS

Presented by

Naraino Majie Nabiilah &

Joorawon Svenia

Date: 21st October2014

Table of Contents• Introduction

• Biography of Paul Ehrlich

• Development of chemotherapy

• Antimicrobial chemotherapy

• General characteristics of antimicrobial drugs

• Determination of antimicrobial drug activity

• Chemotherapeutic agents and their mechanism ofaction

• Factors influencing the effectiveness ofantimicrobial drugs

• Antimicrobial resistance

• Conclusion

INTRODUCTION

INTRODUCTION

• Chemotherapy is the treatment of diseasethrough customized chemical compoundswhich have specific biological targets and donot attack the entire organism which containsthe target.

• Dr. Paul Ehrlich was the first person to treatdisease using chemicals.

• Before him medical treatments were broadspectrum.

• He fathered the idea that a medical treatmentcould be custom made to target the specificcause of disease.

INTRODUCTION

• Paul Ehrlich had been searching for

chemicals that could kill infectious microbes

without harming their human hosts.

• Chemotherapeutic agents (CA) are chemical

agents that are used to treat disease.

• Antibiotics are microbial products or their

derivatives that kill or inhibit susceptible

microorganisms

BIOGRAPHY

BIOGRAPHY

• Born March 14, 1854

• He was a microbe hunter

• Cartooned as Doctor Phantasus

• Known as the father of chemotherapy

• Ehrlich defined chemotherapy as the use of

chemical substances, especially those produced

synthetically, to destroy pathogenic

microorganisms within the body.

• He was a revolutionist-interested in Histological

stain

BIOGRAPHY

• He studies how WBC would stain.

• This led to the discovery of methyl violet

used to stain G+ bacteria and safranin for G-

bacteria.

• In 1878, he had his own laboratory where he

developed method of staining tubercule

bacillus.

• He was infected with tuberculosis in 1887,

went to Egypt and recovered after treatment.

BIOGRAPHY

• Came back and attempted to find a cure for

diphtheria.

• In 1892, diphtheria antitoxin successfully

produced.

• Awarded Nobel prize for this discovery.

• Wanted to produce a magic substance which

will target the desired site only.

• Birth of Antimicrobial chemotherapy.

– Tryptan red aka arsenophenol glycine and

arsenic containing compounds were found

to be effective against trypanosomes.

BIOGRAPHY

• In 1907, Salvarsan was used against

trypanosomes but was uneffective.

• Salvarsan was found to be effective against

syphilis and this remained the most effective

drug until discovery of penicillin by Fleming.

• Chemotherapy research went on while

Ehrlich health was declining.

• Died in August 1915 at the age of 61.

• Now, the concept of Ehrlich chemotherapy is

being employed in modern chemotherapy.

DEVELOPMENT

OF

CHEMOTHERAPY

DEVELOPMENT OF CHEMOTHERAPY

• Paul Ehrlich (1904–1909)—aniline dyes andarsenic compounds

• Gerhard Domagk, and Jacques and ThereseTrefouel (1939)—sulfanilamide

• Ernest Duchesne (1896) discovered penicillin,however, this discovery was not followed up

• Alexander Fleming (1928) accidentallydiscovered the antimicrobial activity ofpenicillin on a contaminated plate; however,follow-up studies did not show the drug wouldremain active in the body long enough to beeffective

DEVELOPMENT OF CHEMOTHERAPY

• Howard Florey and Ernst Chain (1939) aided

by the biochemist, Norman Heatley, worked

from Fleming’s published observations,

obtained a culture from him, and

demonstrated the effectiveness of penicillin

• Selman Waksman (1944)—streptomycin; this

success led to a worldwide search for

additional antibiotics, and the field has

progressed rapidly since then

ANTIMICROBIAL

CHEMOTHERAPY

ANTIMICROBIAL CHEMOTHERAPY

• The foundation of the 20th century

chemotherapy was built on a search of

antiprotozoal agents to be used against malaria

and African sleeping sickness

(trypanosomiasis).

• The chemotherapeutic agents interfere directly

with the multiplication of organisms and in

concentrations not harmful to the host.

ANTIMICROBIAL CHEMOTHERAPY

• Paul Ehrlich formulated the principles of

selective toxicity and recognized the specific

chemical relationship between parasites and

drugs.

• He introduced arsphenamine, an organic

compound of arsenic, as a cure for syphillis

and other spirochetal diseases.

• Likewise, the organic arsenicals, and

synthetic dyes, like trypan blue, were also

found useful in the treatment of

trypanosomiasis.

Selective toxicity is the

ability to kill or inhibit

microbial pathogen with

minimal side effects to the

host

GENERAL

CHARACTERISTICS

OF

ANTIMICROBIAL

DRUGS

GENERAL CHARACTERISTICS OF

ANTIMICROBIAL DRUGS

• Selective toxicity—ability to kill or inhibit

microbial pathogen with minimal side effects

in the host

– Therapeutic dose—the drug level required

for clinical treatment of a particular

infection

– Toxic dose—the drug level at which the

agent becomes too toxic for the host

(produces undesirable side effects)

– Therapeutic index—the ratio of toxic dose to

therapeutic dose: the larger the better

GENERAL CHARACTERISTICS OF

ANTIMICROBIAL DRUGS

• Chemotherapeutic agents can occur naturally,be synthetic, or semisynthetic (chemicalmodifications of naturally occurringantibiotics)

• Drugs with narrow-spectrum activity areeffective against a limited variety ofpathogens;

• Drugs with broad-spectrum activity areeffective against a wide variety of pathogens

GENERAL CHARACTERISTICS OF

ANTIMICROBIAL DRUGS

• Drug can be cidal (able to kill) or static (able to

reversibly inhibit growth)

• Minimal inhibitory concentration (MIC) is the

lowest concentration of the drug that prevents

growth of a pathogen;

• Minimal lethal concentration (MLC) is the

lowest drug concentration that kills the

pathogen

DETERMINING THE

LEVEL OF

ANTIMICROBIAL

ACTIVITY

DETERMINING THE LEVEL OF

ANTIMICROBIAL ACTIVITY

• Dilution susceptibility tests—

– a set of broth-containing tubes are prepared;

– each tube in the set has a specific antibiotic

concentration;

– to each is added a standard number of test

organisms

– The lowest concentration of the antibiotic

resulting in no microbial growth is the MIC

– Tubes showing no growth implies the lowest

concentration of the drug from which the

organism does not recover; this is the MLC

DETERMINING THE LEVEL OF

ANTIMICROBIAL ACTIVITY

• Disk diffusion tests

– Disks impregnated with specific drugs are

placed on agar plates inoculated with the

test organism;

– clear zones (no growth) will be observed

if the organism is sensitive to the drug;

– the size of the clear zone is used to

determine the relative sensitivity;

– zone width also is a function of initial

concentration, solubility, and diffusion

rate of the antibiotic

DETERMINING THE LEVEL OF

ANTIMICROBIAL ACTIVITY

• The Etest®

– Especially useful for testing anaerobic

microorganisms

– Makes use of special plastic strips that

contain a concentration gradient of an

antibiotic;

– Each strip is labeled with a scale of MIC

values;

– After incubation an elliptical zone of

inhibition is observed and its intersection

with the strip is used to determine the MIC

CHEMOTHERAPEUTIC

AGENTS AND THEIR

MECHANISM OF

ACTION

Antibacterial Drugs1. Inhibitors of cell wall synthesis are effective

and selective because bacterial cell walls have

unique structures not found in eukaryotic cells

– Penicillin

– Cephalosporins

– Vancomycin and teicoplanine

Antibacterial Drugs2. Protein synthesis inhibitors exploit the

differences between prokaryotic and eukaryotic

ribosomes

– Aminoglycosides

– Tetracyclines

– Macrolides

– Chloramphenicol

Antibacterial Drugs3. Metabolic antagonists are structural analogs of

metabolic intermediates that act asantimetabolites, inhibiting metabolic pathways;bacteriostatic

– Sulfonamides or sulfa drugs

• inhibit folic acid synthesis in bacteria (humansdon’t synthesize folic acid, so are not affected);

• resistance is increasing and many patients areallergic to these drugs;

• includes p-aminobenzoic acid (PABA)

– Trimethoprim

• synthetic antibiotic that blocks folic acidproduction;

• broad spectrum often combined with sulfa drugs

Antibacterial Drugs

4. Nucleic acid synthesis inhibitors block

enzymes of transcription and translation;

generally not as selectively toxic

– Quinolones

• synthetic drugs that inhibit bacterial DNA

gyrase or topoisomerase II, thereby disrupting

replication, repair, and other processes

involving DNA;

• broad spectrum;

• includes nalidixic acid and ciprofloxacin

(Cipro)

Antifungal Drugs

• Fungal infections are more difficult to treatthan bacterial infections because

– the greater similarity of fungi and hostlimits the ability of a drug to have aselective point of attack;

– furthermore, many fungi havedetoxification systems that inactivatedrugs

• Superficial mycoses are infections ofsuperficial tissues and can often be treated bytopical application of antifungal drugs suchas miconazole, nystatin, and griseofulvin,thereby minimizing systemic side effects

Antifungal Drugs

• Systemic mycoses are more difficult to treat

and can be fatal;

– amphotericin B and flucytosine have been

used with limited success because of its

toxicity;

• Subcutaneous mycoses (e.g., mycetomas) are

treated with a mixture of therapies

Antiviral Drugs• Selectivity is a problem because viruses use the

metabolic machinery of the host

• Antiviral drugs target specific steps of life cycle,including viral uncoating and DNA replication (e.g.,amantadine, vidarabine, acyclovir, cidofovir, andazidothymidine)

• Anti-HIV drugs (e.g., AZT, ddI, 3TC) have fourtargets:

– nucleoside reverse transcriptase inhibitors (NRTIs),

– nonnucleoside reverse transcriptase inhibitors(NNRTIs),

– protease inhibitors (block viral polypeptideprocessing), and

– fusion inhibitors (block viral entry into cell);combinations of drugs often used

• Tamiflu is a neuraminidase inhibitor that is used totreat influenza

Antiprotozoan drugs

• Mechanisms of action for antiprotozoan drugs

are largely unknown; as protozoans and

humans are both eukaryotes, selective toxicity

is difficult to achieve

FACTORS

INFLUENCING THE

EFFECTIVENESS OF

ANTIMICROBIAL

DRUGS

FACTORS INFLUENCING THE EFFECTIVENESS

OF ANTIMICROBIAL DRUGS

• Drug’s ability to reach the site of infection—

this is greatly influenced by

– the mode of administration (e.g., oral,

topical, parenteral),

– by exclusion from the site of infections (e.g.,

blood clots or necrotic tissue protects

bacterium)

• Susceptibility of pathogen—influenced by

growth rate and by inherent properties (e.g.,

whether or not pathogen has target of the drug)

FACTORS INFLUENCING THE EFFECTIVENESS

OF ANTIMICROBIAL DRUGS

• Factors influencing drug concentration in the

body

– must exceed the pathogen’s MIC for the

drug to be effective;

– this will depend on the amount of drug

administered, the route of administration,

the speed of uptake, and the rate of

clearance (elimination) from the body

• Drug resistance has become an increasing

problem

DRUG RESISTANCE

DRUG RESISTANCE

• Bacteria have evolved many strategies for resisting

the action of antibiotics and antibacterial agents.

• Bacteria that produce antibiotics do so to gain a

selective advantage over other competing microbes

in their natural environment.

• If they were sensitive to their own metabolic

products, such a selective advantage would be lost.

• The problem of antibiotic resistance is becoming

increasingly as more and more strains of

pathogenic microorganisms are untreatable with

commonly used antimicrobial agents.

DRUG RESISTANCE

• Mechanisms of drug resistance

– Prevent entrance of drug (e.g., alter drug

transport into cell)

– Pump the drug out of the cell once it has

entered (efflux pump)

– Enzymatic inactivation of the drug

– Alteration of target enzyme or organelle

– Use of alternative pathways and increased

production of the target metabolite.

DRUG RESISTANCE

• Overcoming drug resistance

– Several strategies can be used to

discourage emergence of drug resistance

• administration of high doses,

• simultaneous treatment with more than one

drug,

• limited use of broad-spectrum antibiotics

– Development of new drugs and

exploration of new treatment methods

(e.g., phage treatment of bacterial

infections).

CONCLUSION

• From the basic research of Dr Ehrlich,

modern chemotherapy was developed.

• Many drugs are now being produced to

counteract the pathogens of many diseases.

• Modern chemotherapy is also being

employed in cancer treatment using the

concept of selective toxicity.

• Chemotherapeutic agents against infection

should be used appropriately to prevent

resistance.

REFERENCES

• Antimicrobial Chemotherapy By Roger Finch, Peter Davey, Mark H. Wilcox, William Irving

• Chapter 11. ANTIBIOTICS AND CHEMOTHERAPEUTIC AGENTS BY I.H.Siddiquehttp://compepid.tuskegee.edu/syllabi/pathobiology/microbiology/micro201/chapter11.html

• Anon. General Characteristics of Antimicrobial. http://dev6.mhhe.com/textflowdev/genhtml/0073375268/P8.34.2.htm

• Anon. Antimicrobial drugs. http://classes.midlandstech.edu/carterp/Courses/bio225/chap20/lecture1.htm

• Talaro KP and Chess B. Foundations in Microbiology. Principle of Antimicrobial Therapy. https://www.inkling.com/read/foundations-in-microbiology-talaro-chess-8th/chapter-12/principles-of-antimicrobial

• Todar K. Antibiotics. http://lecturer.ukdw.ac.id/dhira/ControlGrowth/antibiotic.html

THANK YOU