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The history of antibiotics

Andy Parsons gives an introduction to the history of antibiotics.
Antimicrobials have arguably been the most successful form of chemotherapy in the history of medicine. They have contributed, significantly, to the control of infectious diseases and saved millions of lives. The name antimicrobial refers to all agents that act against microbial organisms, including bacteria. This includes antibiotics, which are substances produced by microorganisms that act against other microorganisms. Strictly speaking, antibiotics do not include antimicrobial substances that are made completely in a lab (synthetic), or partly made in a lab (semisynthetic), or those that come from plants. The antibiotic era may not have begun until the 20th century, but antibiotics were still in use in ancient folk medicine.
The earliest traces of antibiotic use date back thousands of years - small amounts of the antibiotic tetracycline were found in human skeletal remains dating back to 350-550 BC. Despite this, we usually associate the beginning of the modern antibiotic era with the names of Paul Ehrlich and Alexander Fleming. The start of the antibiotic age, begins with Paul Ehrlich, a German doctor, who in 1891, used dyes to stain body tissues for examination under the microscope. He found certain cells took up some dyes selectively and argued that if such dyes did not affect other cells, they could be used to target and kill disease-containing microbes, such as syphilis, in the body.
The search was on for suitable dyes to do this - so-called ‘magic bullets’. Ehrlich found that the sixth compound, in the sixth group of compounds, was successful against syphilis - this mixture of two arsenic containing-compounds, sometimes called compound 606, was marketed as Salvarsan in 1910. A key breakthrough came in 1932 when Gerhard Domagk tested thousands of compounds for their bacterial action and discovered that a red dye, subsequently marketed as Prontosil, was effective against bacterial infections in people. Prontosil is an azo dye containing a sulfonamide functional group.
Further research showed that the azo functional group was not required for activity, leading to a range of sulfonamide-containing drugs including sulfanilamide and sulfapyridine, or M&B 693 - this was the drug that cured Winston Churchill of pneumonia during the Second World War. This leads us on to the famous accidental discovery of penicillin, in 1928, by Fleming. The antibacterial properties of mould was known from ancient times, but it was Fleming’s doggedness over many years, in promoting the potential of Penicillium as an antimicrobial, that paid off - the compound was isolated and purified by Florey and Chain who published their results in 1940. Subsequently, their procedure led to the mass production and distribution of penicillin in 1945.
Fleming’s screening method, using inhibition zones in bacteria coated on the surface of agar-medium plates, became widely used in mass screenings for antibiotic-producing microorganisms by researchers. Fleming was also among the first who cautioned about the potential resistance to penicillin if used too little or for too short a period during treatment. The discovery of Salvarsan, Prontosil, and penicillin, were the exemplars for future drug discovery research. The 1950s and 1970s proved to be the golden era of discovery of new classes of antibiotics. Consequently, the most common method for developing new drugs to combat emerging and re-emerging resistance of pathogens to antibiotics has been to modify the structure of existing antibiotics.
The discovery of penicillin by Alexander Fleming in 1928 is a landmark scientific discovery. But how does this rank against other scientific discoveries? In 2010, a survey of more than 400 UK academics highlighted the discovery of DNA, by James Watson and Francis Crick, as the most important breakthrough made by researchers at UK universities. This discovery came above, for example, genetic fingerprinting, the first working computer and the contraceptive pill.
It has been argued that scientific greats, like Fleming, can be positive role models for aspiring scientists, helping them understand different ways to succeed with examples for overcoming obstacles. Others argue that when someone is held up as a role model, nuances can be lost, from failed experiments to important collaborations with other researchers. This can give an incomplete, often unrealistic and sometimes intimidating picture, of what scientific research is like.
What do you think about using scientists as role models and what scientist has inspired you most? Perhaps you will pick Newton, Pasteur, Curie or Einstein? At York, we have a special affection for Professor Dorothy Hodgkin, who was awarded the Nobel Prize for Chemistry in 1964. Professor Hodgkin visited the University of York frequently between 1976 and 1988, to write up the findings of a total of more than 30 years’ research into insulin structures. One of our research buildings, built in 2012, bears her name.
Those of you considering picking a cult TV scientist may like to know that, in 2004, the ‘Muppet Labs’ Dr Bunsen and his assistant Beaker topped a poll (based on more than 40,000 votes) for the UK’s favourite cult TV boffin!

By chance?

Interestingly, the discovery of penicillin by Fleming was accidental. Before going on holiday he left some unsterilised agar plates near an open window – luckily a common mould landed on the plates and just before washing them, Fleming noted a clear ring in the jelly around some of the spots of mould, showing inhibited bacterial growth. A significant number of other notable scientific discoveries have been made by chance, or serendipitiously, and we will return to this topic in week 4. In the meantime, here are some other biologically active compounds discovered by accident.
Denatonium benzoate (Bitrex) – during a research programme aimed at developing a new local anaesthetic, similar to lidocaine, scientists accidentally discovered the most bitter substance known. It is in the Guinness World Records. Despite having very similar structures, lidocaine and denatonium benzoate have vastly different biological effects. Bitrex is added to numerous household products, from antifreeze to liquid laundry detergents, to prevent accidental posioning. Even cards for the Nintendo Switch gaming console are coated in Bitrex, to deter children from ingesting them (due to their small size).
Rogaine (Minoxidil) – first marketed as Loniten, a medicine used to treat high blood pressure, but users observed it darkened their hair and caused hair growth; a more dilute formulation is now sold as a direct application to the scalp, to treat hair loss.
Somnote (Chloral hydrate) – in the body, chloral hydrate (Cl3C–CH(OH)2) was expected to form chloroform (CHCl3), which could induce sleep; no chloroform is formed, but chloral hydrate was found to be a sedative becoming the world’s first mass produced synthetic hypnotic (fans of old movies will know it as a “Mickey Finn”).
Also, the discovery of the antibiotic azithromycin is interesting. After 8 years of hard work to find an improved version of the antibiotic erythromycin (which stops bacterial cells from growing and multiplying by interfering with their ability to make proteins), the chemical company Pfizer was preparing to end its research into compounds with large rings (called macrolides). However, as can happen in medicinal research and development, the week before the program was to be formally ended, the team hit upon a novel compound, which was called azithromycin – this is not only a potent antibiotic effective against a variety of bacteria, but, fortuitously it is delivered directly to the site of infection!
Finally, see if you can recognise the six famous scientists in the face puzzle in the downloads section below – we look forward to reading your suggestions.
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Exploring Everyday Chemistry

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