ANTIBIOTICS

What is an Antibiotic?

• 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 micro-organisms .

Pathogenic Microbial Discoveries

Year Microbe discovered

1880-82 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 disease-causing 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

Pfizer LtdPfizer Ltd

Penicillin ProductionPenicillin Production

What does the penicillin fungus What does the penicillin fungus need to grow?need to grow?

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 SilversideAlan 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 LtdPfizer 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 spin-dryer – 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 LtdPfizer 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.

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.

Penicillin derivatives

Major antibiotics of clinical significance include the -lactam antibiotics penicillin and cephalosporin and the tetracyclines

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