Understanding antibiotic resistance
Understanding antibiotic resistance

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Understanding antibiotic resistance

2.1 Producing natural antibiotics

Natural antibiotics are complex chemicals which are synthesised stepwise by the bacteria or fungi that produce them in a series of enzyme-catalysed reactions. The starting compounds are usually products of the cell’s mtabolism – chemical reactions that allow a cell to obtain the energy and nutrients it needs to grow and survive. These essential compounds, or primary metabolites, are made in the exponential phase of growth. Antibiotics, however, are secondary metabolites, that is they are products of metabolism that are not essential for growth.

You might recall from Week 1 that bacteria and fungi produce antibiotics to prevent competing organisms using nutrients and other resources.

  • Why aren’t antibiotics produced during the exponential stage of growth?

  • The exponential stage is when abundant resources allow rapid growth, so only primary metabolites are made. During the stationary phase, competition for nutrients increases and resources are diverted away from growth to make antibiotics.

In manufacturing, pure cultures of antibiotic-producing bacteria and fungi are grown in huge bioreactors (containing thousands of litres) in a process known as batch fermentation. Batch fermentation favours antibiotic production by limiting the time that cells spend in the exponential growth phase. The antibiotic products are then harvested and purified.

As you will discover in Activity 1, this process was not always so streamlined.

Activity 1 Commercial production of penicillin – Part 1

Allow about 10 minutes

When Alexander Fleming accidentally discovered penicillin in 1928, he had no idea what to do with it or how to reproduce it. This was left for other researchers to do.

First, watch the video below about how penicillin was ‘rediscovered’ ten years later by Howard Florey and his Oxford-based research team.

Download this video clip.Video player: Video 2
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Transcript: Video 2 Penicillin rediscovered.

WOMAN:
Behind this door is the original lab of the pioneering Oxford scientist Howard Florey. And it was in here that a team of brilliant minds turned Fleming's rather unexpected discovery into a miracle cure.
This is the room where antibiotics were truly invented at the dawn of the Second World War. The team invented a way to purify the mould juice by combining it with ether and alkalines that drew away the harmful elements, creating an antibiotic pure enough for humans to take.
Scientist and historian Dr. Eric Sidebottom was a pupil of the men involved. Clearly, if it was going to do any good at all to the masses it had to be mass produced. So were they able to develop penicillin here in Great Britain?
DR. ERIC SIDEBOTTOM:
Yes, to some extent they were, but Florey was always worried that he couldn't really persuade the British pharmaceutical industry to get involved. They were already committed to the war effort.
So Florey made this difficult decision to take the problem to America. And the Americans did help. They increased production very considerably. They found a better strain of penicillium on a local melon in the market. They also managed to get it growing in a huge suspension tank, in a big tank. Whereas in Oxford, we'd grown it in bedpans.
End transcript: Video 2 Penicillin rediscovered.
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Now answer the following questions, based on the video.

  1. What was the first key thing that Florey’s team achieved with penicillin?
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  1. Why were British pharmaceutical companies reluctant to help develop penicillin?
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  1. What did the American pharmaceutical companies achieve with penicillin?
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Answer

  1. The penicillin was purified to a level that was safe for use in humans.
  2. In the late 1930s, British companies were prioritising the war effort.
  3. They increased production and isolated a more powerful Penicillium mould.

In the UK, Florey’s team had managed to purify penicillin and treat a bacterial infection. This was a major achievement, but the team was hampered by a lack of funding and equipment, and yields of the drug remained poor. After the move to the USA, the research picked up pace. By 1943, the production of penicillin was under way with the new, more powerful strain growing in a different medium – corn syrup. However, the production process was still inefficient and yields of penicillin remained low.

The second part of Activity 1 looks at the changes made to the manufacturing process that led to much higher yields of penicillin.

Activity 1 Commercial production of penicillin – Part 2

Allow about 10 minutes

The video below explains how the key to increased productivity was growing the Penicillium mould in a liquid, rather than as a layer at the bottom of a large flat-bottomed flask.

As you watch the video, consider the following questions.

  1. What was the advantage of a liquid medium?
  2. Why was it critical to control the level of oxygenation?
Download this video clip.Video player: Video 3
Skip transcript: Video 3 Mass production of penicillin.

Transcript: Video 3 Mass production of penicillin.

[MUSIC PLAYING]

MICHAEL MOSLEY:
But despite these improvements, the inefficiency of the actual production process meant that by 1943 there were still only enough penicillin to treat a lucky few.
MAN 1:
The standard techniques were large white bottom flasks because you had a single layer of mould producing, the yields from each flask were minimal.
MICHAEL MOSLEY:
And the need for penicillin had never been more urgent. D-day, the greatest amphibious invasion in history, was only months away. Casualties were going to be horrific.
MAN 2:
Penicillin was the US military's second top research priority after the Manhattan Project, after nuclear weapons.
MICHAEL MOSLEY:
It was then that a small chemical company based in this building in Brooklyn, called Pfizer, got involved. Now, these days, Pfizer is better known for its anti-impotence drug, Viagra. But back then, they produced citric acid used in fizzy drinks.
Now, they realised, as everyone else had, that if you just grow penicillin on the surface of a liquid then that is going to be really inefficient. What you want to do is grow it throughout the liquid. The problem is that penicillin needs oxygen to grow. So they came up with a solution which they hoped would work.
MAN 1:
The oxygenation came with a tube introduced into the medium into which oxygen was pumped. But you couldn't put too much, and you couldn't put too little. So learning how much was right was key.
MICHAEL MOSLEY:
There was absolutely no guarantee the technique would work. But the company took a gamble. Because of wartime shortages, they had to convert an old Brooklyn ice factory, scrounging a boiler from Indiana and a lift from Long Island.
With just two months to go before D-day, they installed 14 giant fermentation tanks. Then they added the corn syrup and the cantaloupe mould before turning on the air.
The results were spectacular. They soon began producing five times as much penicillin as originally planned. By June 1944, the D-day invasions, there was enough penicillin for every injured soldier. And most of it was produced right here in the Pfizer plant in Brooklyn.
End transcript: Video 3 Mass production of penicillin.
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Discussion

  1. The liquid culture allowed more Penicillium to be grown and more penicillin to be produced.
  2. If the oxygen level is too low, Penicillium will die because it needs oxygen to grow. Too much oxygen can be toxic to fungi and bacteria – as it can be to humans.
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