Antibiotics

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Antibiotics Biosynthesis, mechanism of action
and resistance Malcolm G. P.
Page malcolm.page_at_basilea.com
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Topics for Discussion
Early chemotherapy and antibiotic
discovery Antibiotic classes by
target Antibiotic discovery today
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Timetable

• 4 th November Introduction
• 11th November Antibiotics
• 18th November Antibiotics
• 25th November Antibiotics questionnaire
• 2nd December Antibiotics evaluation
• 9th December Antibiotics
• 16th December Conclusion Exam
• Exam format open book, multiple-choice

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3000 Years of Chemotherapy - fungi
Ancient civilizations around the world
independently discovered that moulds could be
used to cure infections. The people believed the
moulds drove away evil spirits that cause
disease.
Chinese used mouldy soybean curd to treat boils,
furuncles and carbuncles. (S. aureus
infections). South American Indians wore sandals
furry with mould to treat and prevent foot
infections (Fungal infections). Central
Europeans kept stocks of mouldy bread for
treating cuts, sores and fevers (Bacterial
infections).
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3000 Years of Chemotherapy Plants

• Stone age man in Iraq buried with Yarrow,
  Hyacinth and Marsh Mallow root
• Yarrow antihaemorrhagic , antiseptic
• Hyacinth antihaemorrhagic diuretic
• Marsh Mallow root anti-inflammatory, wound
  healing

Althea officinalis
Achillea millefolium
Hyacinthus nonscriptum
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Medieval Chemotherapy
Strong tradition for using plants to treat
infections developed in China, Asia and
Americas. Less common in Europe, where the
attention was on other diseases Foxglove
(digitalin), willow bark (salicylates). In the
European Middle Ages focus was on inorganic
treatments (e.g. mercuric chloride for syphilis)
S. American Indians chewed roots, bark and leaves
and berries of many plants of cinchona tree
for malaria coca bush for rheumatism
altitude sickness ipecac plant for dysentery
1627 Interest re-awakened by Jesuit missionaries
in Peru who noted the Amerindian use of
Cinchona bark as an anti-malarial agent.
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Evolution of Gin Tonic
17th century
Jenever distilled by dutch herbalist from grain
juniper berries (blood purifier)
Cinchona bark extract first used to treat malaria
by europeans
1747, proved that fresh fruit prevents
scurvy 1795, Royal Navy starts routine issue of
lime juice
18th century
Gin lime juice adopted by Royal Navy (Gimlet)
19th century
Tonic water Extract of javan C. natida bark Used
to treat malaria and fevers by British
Indian Army
Gin, lime tonic water combined to take away the
bitter taste of quinine
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The Rediscovery of Antibiotics
1871 Lister noted that bacteria did not grow in
urine samples contaminated with mould. 1877
Pasteur showed that anthrax bacilli in animals
could be rendered harmless by injections of soil
bacteria and moulds. 1887 Emmerich Low
developed a cell extract that became the first
antibiotic substance to be used in
hospitals. 1889 Vuillemin noted that fungi and
yeasts could destroy bacteria - a process he
called antibiosis. 1897 Kronig, Paul Ehrlich
started systematic testing of chemicals for their
activity against bacteria and other
microbes. 1924 Gratia Dath started screening
soil microbes for antibacterial activity.
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Discovery of Synthetic Antibiotics Sulfonamides

1913 Eisenberg discovered the antibacterial
properties of the dye chrysoidine but it was
too toxic to use. 1932 Domagk showed that the
bright red dye prontosil rubrum was relatively
non-toxic and protected mice against
streptococcal infections. 1935 Domagk, Klarer
and Mietzsch identified a breakdown product of
prontosil rubrum that was formed in the mice
(sulfonamide) and had antibiotic activity. 1939
Domagk received the Nobel Prize in
Medicine for discovering the sulfonamides. By
1945 the pharmaceutical industry had produced
5488 sulfonamides.
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Discovery of Natural Antibiotics - Penicillins
1929 Alexander Fleming demonstrated inhibition of
Staphylococcus aureus by the mould Penicillium
notatum.
Fleming noted tiny droplets of fluid began to
form on the mould. He drew off the liquid and
found that it could kill germs in a test-tube.
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Discovery of Penicillin

1932 Country doctor Cecil Paine tried
Flemings droplets on patients. Showed his
successful results to Howard Florey who was
looking for a new project. 1938-40 Florey
Chain isolated the active principle - penicillin
- from the droplets and tested it. The
first patients treated showed improvement but it
was not possible to make enough material to
complete the cure. 1945 Fleming, Chain
and Florey received the Nobel Prize in Medicine.
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Industrial Exploitation of Penicillin

1941 Penicillin production transferred to US
Low yield remained a problem. 1942 New
isolate discovered on a mouldy
canteloupe. Produces 200
times as much. Pfizer starts industrial
fermentation
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The "Golden Era" of Antibiotic Discovery

1940 Selman Waksman systematically isolates
antimicrobial substance from soil
organisms actinomycin (1940) clavacin (1942),
streptothricin (1942), streptomycin (1943)
grisein (1946) neomycin (1948), Proposed
term "antibiotic" Streptomycin and neomycin
make major contribution to the treatment of
Gram-negative bacteria and tuberculosis 1952
Waksman receives the Nobel Prize in Physiology or
Medicine
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Sources of Natural Antibiotics
Cemetery soil Chlorotetracycline
Mouldy food Penicillin
Forest soils Erythromycin Chloramphenicol Vancom
ycin
Andean soil Streptomycin
Mediterranean sewage Cephalosporin
Infected wounds Bacitracin
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Antibacterial Agents Available Today
Synthetic
Daptomycin
Natural origin
Oxazolidinones
Carbapenems
Discovered but not used
Fluoroquinolones
Cephamycins
Lincosamides
Streptogramins
Trimethoprim
Cephalosporins
Quinolones
Vancomycin
Macrolides
Chloramphenicols
Tetracyclines
Aminoglycosides
Penicillins
Sulfonamides
2000
1930
1940
1950
1960
1970
1980
1990
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Traditional Sources
Origins of medicines derived from nature
Antibacterials
Antifungals
Non-Actinomycetes Actinomycetes Fungi Higher
Plants
Anti-protozoan Human medicines
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Targets for Anti-bacterial Drugs
Cell wall Cephalosporins, Penicillins Vancomycin
Nucleoid Fluoroquinolones
Cell division
Ribosome Macrolides Tetracyclines
Cell membrane Antiseptics Triclosan
Metabolism sulfa drugs, anti-folates