Transcript antibiotics

ANTIBIOTICS
What is an Antibiotic?
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An antibiotic is a selective poison.
It will kill the desired bacteria, but not the cells in
human body.
Each different type of antibiotic affects different
bacteria in different ways.
• For example, mode of action of antibiotics :
1. inhibit a bacteria's ability to turn glucose into
energy,
2. inhibit bacteria's ability to construct its cell wall
 the bacteria dies instead of reproducing
History
• The latter half of the 19th century, Pasteur
noted the antagonistic effect of other bacteria on
the anthrax organism and pointed out that this
action might be put to therapeutic use
• Meanwhile the German chemist Paul Ehrlich
developed the idea of selective toxicity: that
certain chemicals that would be toxic to some
organisms, e.g., infectious bacteria, would be
harmless to other organisms, e.g., humans.
History (cont.)
• In 1928, Sir Alexander Fleming, a Scottish
biologist, observed that Penicillium
notatum, a common mold, had destroyed
staphylococcus bacteria in culture.
• In 1939 the American microbiologist René
Dubos demonstrated that a soil bacterium
was capable of decomposing the starch
like capsule of the Pneumococcus
bacterium
History (cont.)
• Dubos then found in the soil a microbe, Bacillus
brevis, from which he obtained a product,
tyrothricin, that was highly toxic to a wide range
of bacteria. Tyrothricin, a mixture of the two
peptides gramicidin and tyrocidine, was also
found to be toxic to red blood and reproductive
cells in humans but could be used to good effect
when applied as an ointment on body surfaces.
History (cont.)
• Penicillin was finally isolated in 1939, and
in 1944 Selman Waksman and Albert
Schatz, American microbiologists, isolated
streptomycin and a number of other
antibiotics from Streptomyces griseus.
Penicillin
• The wonder drug
• The first antibiotic popularly known
• The first antibiotic produced and used
on a massive scale
• The pioneer of chemotherapy
Discovery of Penicillin
Background
• Works of Louis Pasteur and Robert Koch,
helped elucidate the connection between
infectious diseases and the invasion of the
body by bacteria and other microorganisms .
Pathogenic Microbial Discoveries
Year
1880-82
Microbe
discovered
Typhoid
1883
Cholera
1884
Tetanus
1886
Pneumonia
1894
Plague
History of penicillin
• In 1871, Joseph Lister ( antiseptic practice
surgery) - a mold in a sample of urine - inhibiting
bacterial growth
• In 1875 John Tyndall - a species of Penicillium
caused some of his bacteria to burst
• In 1877 Louis Pasteur and Jules Joubert airborne microorganisms could inhibit the growth
of anthrax bacilli
History (contd.)
• Ernest Duchesne in 1897 focused on the
interaction between E. coli and Penicillium
glaucum .
• Inoculating mold and typhoid bacilli -prevented
contraction of typhoid in animals. But, he died of
T.B before he could complete his research.
• Experiments carried out by Emmerich and Loew
(1899) and later by Gratia and Dath and others
did not give any favorable results.
History (contd.)
• Instead various forms of vaccination and
serum treatment were evolved.
• The first Nobel Prize for Physiology or
Medicine in 1901 was given for serum
therapy for diphtheria.
• Human and animal bodies - produce
protective substances in the fight against
the invaders.
Sir Alexander Fleming
• Born on August 6th,1881 at Lochfield,
Scotland in a farmer’s family .
• He had his early days spent more in the
farms but was sound in his fundamental
education.
• 1895-The untimely death of his father and
the success of the medical practice of his
step-brother Tom had him relocated to
London.
Sir Alexander Fleming
• 1895 –He attended the Polytechnic School
in Regent Street .
• 1896-1900- He worked as a clerk in a
shipping firm.
• 1900- In 1900, when the Boer War broke
out joined the Scottish regiment but
never saw the combat.
Sir Alexander Fleming
• Later encouraged by his brother and
supported by the money he received from
an Uncle’s demise he looked towards a
medical career.
• 1901-He won a scholarship to St. Mary's
Hospital Medical School, London
University, Paddington and joined it.
• He qualified with distinction and received
his degree in 1906
Sir Alexander Fleming
• His switch to bacteriology was even more
surprising: if he took a position as a surgeon, he
would have to leave St. Mary's.
• The captain of St. Mary's rifle club knew that and
was desperate to improve his team. Knowing
that Fleming was a great shot he did all he could
to keep him at St. Mary's.
• He worked in the Inoculation Service and he
convinced Fleming to join his department in
order to work with its brilliant director -- and to
join the rifle club.
Sir Alexander Fleming
• 1906- Fleming joined the Inoculation Department as
medical bacteriologist under the direction of Sir
Almroth Wright.
• He made the St. Mary's Hospital Medical School his
professional home for the rest of his life.
• 1914-Flemming became a lecturer at St.Mary’s.
• 1914-1918- Served as Captain in W W 1
Sir Alexander Fleming
• 1918 -He returned to St.Mary's.
• 1928- He was elected Professor of the
School in 1928
• 1943-He was elected Fellow of Royal
Society.
• 1944-Flemming was knighted.
• 1945-Received his Nobel Prize.
Sir Alexander Fleming
• 1948-Elected the Emeritus Professor of
Bacteriology, University of London.
• 1951-54- He was Rector of Edinburgh
University.
• Died on March 11th,1955
Antiseptics of that period
• During World War I- wound-research
laboratory in Boulogne, France.
• Chemical antiseptics like carbolic acid
(phenol) do not sterilize jagged wounds;
rather, pus has its own antibacterial powers.
• He was able to show that chemical
antiseptics in dilutions harmless to bacteria
actually damage white blood corpuscles
(leukocytes)—the body's first line of defense.
Lysozyme Discovery
• Fleming looked for -a chemical that could help
fight microbe infections.
• After war in 1920, back in St.Mary’s,Fleming
searched for an affective antiseptic.
• He discovered Lysozyme, in nasal mucus . Its
an enzyme found in many body fluid, like tears,
etc.
• It is a natural antibacterial not effective against
the stronger infectious agents.
Lysozyme’s Activity
Lysozyme
• Lysozyme, in its natural state, seemed to
be more effective against harmless
airborne bacteria than against diseasecausing bacteria.
• attempts to concentrate it, proved
unsuccessful.
• Fleming continued his research of finding
a better and less toxic antiseptic and
antibacterial.
The Chanced Discovery
• Fleming's legendary discovery of penicillin
occurred in 1928, while he was
investigating staphylococcus, a common
bacteria then caused diseases ranging
from boils to disastrous infections.
Fleming at his usual work
The Halo of Penicillin
• He left a culture plate smeared with
Staphylococcus bacteria on his lab
bench while he went on a two-week
holiday.
• When he returned, he noticed a clear
halo surrounding the yellow-green
growth of a mold that had accidentally
contaminated the plate.
The Halo of Pencillin
The culture-plate
How This Happened
• Luckily, Fleming had not stored his
culture in a warm incubator. London
was then hit by a cold spell, giving the
mold a chance to grow.
• Later, as the temperature rose, the
Staphylococcus bacteria grew,
covering the entire plate--except for the
area surrounding the moldy
contaminant.
Fleming’s Deduction
• Fleming correctly deduced -mold must
have released a substance - inhibited
the growth of the bacteria.
• He was never clear on his
observations. The evidence of the first
culture, which he photographed
indicated that Fleming observed lysis,
the weakening and destruction of
bacteria—as in his lysozyme studies.
Penicillin and Lysozyme Activity
Penicillin Identified
• He discovered that the antibacterial
substance was not produced by all molds,
only by strain of Penicillium notatum
• Although he could not isolate it, he named
the active substance “penicillin.”
• He studied methods of producing the impure
product and determined its stability at
different temperatures and over various
lengths of time.
Penicillin is Non-Toxic
• Fleming found that penicillin was not toxic
to animals and that it did not harm white
blood cells (leucocytes) by injecting
healthy mice extract from the mold growth.
Streptomyces
Test for penicillin activity
Test for
streptomycin
producers
Production of
antibiotics
Production of Penicillins
and Tetracyclines
Penicillin Production
What does the penicillin fungus need
to grow?
 Pfizer Ltd
Penicillium
This is Penicillium – the fungus
that produces penicillin, the
first of the antibiotic ‘wonder
drugs’. Antibiotics kill bacteria
without harming humans.
Penicillin has saved many,
many millions of lives since it
was discovered – and treated
millions of minor infections as
well.
 Alan Silverside
As a fungus,
Penicillium cannot
photosynthesise. A
solution containing
corn liquor
(containing sugar),
nitrate fertilisers
and yeast extract is
added to the fungus
in a giant tank or
fermenter. This
provides all of the
required nutrients,
and fermentation
begins.
 Pfizer Ltd
Temperature,
oxygen
concentration
and pH are
controlled in
the fermenter.
Large paddles
swirl the
medium
around to keep
everything
well mixed.
Over the next
140 hours the
fungus will
grow and start
to produce
penicillin.
The kinetics of the penicillin
fermentation with Penicillium
chrysogenum.
After about 140
hours roughly 30%
of the mixture will
be drained off and
fresh nutrient added.
The material that
has been drained off
is passed to a
separator.
Why wait until 140
hours before this is
done?
• All of the antibiotics are typical secondary
metabolites  produced in stationary
phase
The separator acts
a bit like a spindryer – a vacuum
draws mixture onto
a rotating drum.
The drum is porous
so the dissolved
penicillin passes
through into the
centre while the
fungal filaments are
stuck on the
outside. These
filaments are
removed by a blade
as the drum
rotates.
 Pfizer Ltd
The filtered liquid with the dissolved penicillin
is treated with potassium salts. This
precipitates the penicillin out of solution. This
precipitate can then be collected by filtering
and the powder produced can be as high as
99.5% pure penicillin.
Penicillin and the
other antibiotics
which have been
discovered are some
of the most useful
medicines we have.
Doctors all over the
world prescribe them
to save patients from
the effects of
bacterial disease.
If the new antibiotic is biologically active in
vivo, the industrial microbiologist may
genetically modify the producing strain to
increase yields to levels acceptable for
commercial development  strain
improvement
If the penicillin fermentation is carried out
without addition of side-chain precursors,
the natural penicillins are produced. The
fermentation can be more directed by
adding to the broth a side-chain precursor
so that only one desired penicillin is
produced.
Penicillin derivatives
1. The product formed under these
conditions is referred to as a
biosynthetic penicillin.
2. To produce the most useful penicillins,
those with activity against gram-negative
Bacteria, a combined fermentation and
chemical approach is used that leads to
the production of semiynthetic
penicillins.
Major antibiotics of clinical significance include the -lactam
antibiotics penicillin and cephalosporin and the tetracyclines
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