Chapter 9 – antimicrobial chemotherapy (L1)
Development of chemotherapy
Paul Ehrlich (1854 – 1915) was a German
medical scientist who made significant
contributions to hematology, immunology,
and chemotherapy. He developed the
concept of selective toxicity, which led to Penicillin
the idea of a “magic bullet” – a drug that • The first true antibiotic because it is a natural microbial
could target specific microbes without harming healthy cells. product
Ehrlich’s research focused on testing arsenical dyes for killing • First discovered by Ernest Duchesne (1896), but discovery
microbes, and he discovered the first eHective treatment for lost
syphilis. His work on the therapeutic properties of dyes and the • Accidently discovered by Alexander Fleming (1928)
magic bullet concept became the foundation of modern - Observed penicillin activity on contaminated plate
pharmaceutical research. Ehrlich was awarded the Nobel Prize in - Did not think it could be developed further
Physiology or Medicine in 1908 for his contributions to - Could not demonstrate that penicillin remained active
immunology. in vivo long enough to destroy pathogens
Sahachiro Hata was a Japanese bacteriologist who collaborated - EHectiveness demonstrated by Florey, Chain, and
with Paul Ehrlich in his quest to develop a drug treatment for Heatley (1939)
syphilis that specifically targeted the pathogen without aHecting - Flemmingm, Florey, and Chain received Nobel Prize in
normal host cells. In 1909, Hata went to work in Ehrlich’s 1945 for discovery and production of penicillin
laboratory, the National institute for Experimental Therapeutics, in
Frankfurt, Germany to help Ehrlich develop a “magic bullet” drug h
that would target syphilis bacterium. Hata and Ehrlich performed
experiments on 605 chemical compounds before finding the 606th
compound, arsphenamine, which was eHective against syphilis.
Arsphenamine, also known as Salvarsan, was the first eHective
treatment for syphilis and represented a turning point in the
development of chemotherapy. Hata’s and Ehrlich’s work on
arsphenamine was a significant contribution to the field of
pharmacology
, Later discoveries - Therapeutic dose: drug level required for clinical
treatment
• Streptomycin, from Streptomyces griseus an antibiotic !"#$% '"()
active against tuberculosis, was discovered by Selman - Therapeutic index: therapeutic index = !*)+,-).!$% '"()
Waksman (1944) after screening > 10 000 strains of soil o The larger the therapeutic index, the better the
bacteria and fungi chemotherapeutic agent in general
- Nobel prize was awarded to Waksman in 1952 for this o A drug that disrupts a microbial structure or
discovery function not found in host cells often has greater
• By 1953: chloramphenicol, oxytetracycline, neomycin and selective toxicity and a higher therapeutic index
tetracycline isolated from Streptomyces species o Penicillin – inhibits bacterial cell wall
• Why would a micro-organism secrete an antibiotic? peptidoglycan synthesis – host cells lack
- Are common metabolic products or aerobic bacteria peptidoglycan – high therapeutic index
and fungi • Side eLects: undesirable eHects of drugs on host cells
- In nature some microbes produce substances that • Narrow spectrum drugs: active against only a few diHerent
inhibit the growth of other micro-organisms that might pathogens
compete for the same resources, in the same habitat • Broad-spectrum drugs: active against many diHerent
(antagonism) antibiotic producers presumably enjoy pathogens
less competition for nutrients and space • -cidal agent – kills microbes
• -static agent – inhibits growth of microbes
Natural antibiotics = antibiotics produced by micro-organisms
• EHectiveness expressed in 2 ways:
Semisynthetic antibiotics = antibiotics further chemically - Minimal inhibitory concentration (MIC)
modified o Lowest concentration of drug that inhibits growth
of pathogen
- Minimal lethal concentration (MLC)
General characteristics of antimicrobial drugs o Lowest concentration of drug that kills pathogen
• Selective toxicity (“magic bullet”)
- Should kill or suppress the pathogen without damage to
the host
• Are expresses as:
- Toxic dose: drug level at which drug becomes too toxic
for patient (i.e. produces side eHects)
Development of chemotherapy
Paul Ehrlich (1854 – 1915) was a German
medical scientist who made significant
contributions to hematology, immunology,
and chemotherapy. He developed the
concept of selective toxicity, which led to Penicillin
the idea of a “magic bullet” – a drug that • The first true antibiotic because it is a natural microbial
could target specific microbes without harming healthy cells. product
Ehrlich’s research focused on testing arsenical dyes for killing • First discovered by Ernest Duchesne (1896), but discovery
microbes, and he discovered the first eHective treatment for lost
syphilis. His work on the therapeutic properties of dyes and the • Accidently discovered by Alexander Fleming (1928)
magic bullet concept became the foundation of modern - Observed penicillin activity on contaminated plate
pharmaceutical research. Ehrlich was awarded the Nobel Prize in - Did not think it could be developed further
Physiology or Medicine in 1908 for his contributions to - Could not demonstrate that penicillin remained active
immunology. in vivo long enough to destroy pathogens
Sahachiro Hata was a Japanese bacteriologist who collaborated - EHectiveness demonstrated by Florey, Chain, and
with Paul Ehrlich in his quest to develop a drug treatment for Heatley (1939)
syphilis that specifically targeted the pathogen without aHecting - Flemmingm, Florey, and Chain received Nobel Prize in
normal host cells. In 1909, Hata went to work in Ehrlich’s 1945 for discovery and production of penicillin
laboratory, the National institute for Experimental Therapeutics, in
Frankfurt, Germany to help Ehrlich develop a “magic bullet” drug h
that would target syphilis bacterium. Hata and Ehrlich performed
experiments on 605 chemical compounds before finding the 606th
compound, arsphenamine, which was eHective against syphilis.
Arsphenamine, also known as Salvarsan, was the first eHective
treatment for syphilis and represented a turning point in the
development of chemotherapy. Hata’s and Ehrlich’s work on
arsphenamine was a significant contribution to the field of
pharmacology
, Later discoveries - Therapeutic dose: drug level required for clinical
treatment
• Streptomycin, from Streptomyces griseus an antibiotic !"#$% '"()
active against tuberculosis, was discovered by Selman - Therapeutic index: therapeutic index = !*)+,-).!$% '"()
Waksman (1944) after screening > 10 000 strains of soil o The larger the therapeutic index, the better the
bacteria and fungi chemotherapeutic agent in general
- Nobel prize was awarded to Waksman in 1952 for this o A drug that disrupts a microbial structure or
discovery function not found in host cells often has greater
• By 1953: chloramphenicol, oxytetracycline, neomycin and selective toxicity and a higher therapeutic index
tetracycline isolated from Streptomyces species o Penicillin – inhibits bacterial cell wall
• Why would a micro-organism secrete an antibiotic? peptidoglycan synthesis – host cells lack
- Are common metabolic products or aerobic bacteria peptidoglycan – high therapeutic index
and fungi • Side eLects: undesirable eHects of drugs on host cells
- In nature some microbes produce substances that • Narrow spectrum drugs: active against only a few diHerent
inhibit the growth of other micro-organisms that might pathogens
compete for the same resources, in the same habitat • Broad-spectrum drugs: active against many diHerent
(antagonism) antibiotic producers presumably enjoy pathogens
less competition for nutrients and space • -cidal agent – kills microbes
• -static agent – inhibits growth of microbes
Natural antibiotics = antibiotics produced by micro-organisms
• EHectiveness expressed in 2 ways:
Semisynthetic antibiotics = antibiotics further chemically - Minimal inhibitory concentration (MIC)
modified o Lowest concentration of drug that inhibits growth
of pathogen
- Minimal lethal concentration (MLC)
General characteristics of antimicrobial drugs o Lowest concentration of drug that kills pathogen
• Selective toxicity (“magic bullet”)
- Should kill or suppress the pathogen without damage to
the host
• Are expresses as:
- Toxic dose: drug level at which drug becomes too toxic
for patient (i.e. produces side eHects)
