The story of antibiotics

The discovery of antibiotics has been a game-changer for modern medicine in fighting off infections. Priya Kulasagaran tracks the colourful history of antibiotics, how they work, and why excessive antibiotic use can be too much of a good thing

Most people who have attended a secondary school science class can recall the discovery of the modern antibiotic: in 1928, a Scottish bacteriologist stumbled across Penicillin almost by accident when he came across a mould sample in his home-lab. That scientist, Sir Alexander Fleming, earned the Nobel Prize in 1945 for his find.

Aside from being the first drug to fight off bacterial infections, Fleming’s discovery was instrumental to the growth of the pharmaceutical industry as we know it today. All this from a forgotten Petri dish. Of course, the real story is a bit more complicated.

A few years back, scientists examining the 2,000-year-old bones of ancient Sudanese Nubians found that the remains contained substantial amounts of tetracycline, an antibiotic that was first commercially available in the 20th century. Publishing their results in the American Journal of Physical Anthropology in 2010, the scientists proposed that the Nubians were intentionally consuming the antibiotic — through their beer. This practice is not as hedonistic as it sounds, as the researchers say the beer was not so much an intoxicating elixir as it was a thick “sour porridge substance”.

Throughout history, people have been using antibiotics before even realising the existence of bacteria. One of the oldest medical texts, an ancient Egyptian papyrus translated in the 1920s, advises using mouldy bread to treat wounds. The practice, similar to the idea behind penicillin, was also advocated in ancient China, Serbia, and Greece.

The pre-penicillin discovery

In late August 1909, Paul Ehrlich and Sahachiro Hata injected a syphilis-infected rabbit with the 606th version of their chemical preparation. For two years, the scientists had been painstakingly brewing numerous versions of Atoxyl, an arsenic-like drug, isolating various compounds and testing them one by one. This time, to the relief of syphilis victims, they found a brew that worked.

Syphilis, a sexually transmitted disease caused by the bacteria Treponema pallidium, is now easily treatable with a short course of antibiotics. For hundreds of years however, the illness was a source of fear and considered incurable. Aside from weeping sores which seemed to slowly eat away at the flesh, worst-case scenarios left patients insane as the disease attacked the brain. Treatment for syphilis was almost as bad as the disease itself; patients were given mercury to either eat, inhale or rub over their bodies.

Before he set his sights on solving syphilis, Ehrlich was trying to figure out how antibacterial chemicals worked. The German physician found that some chemical dyes coloured certain bacteria but not other cells. This led him to theorise that there must be a “magic bullet” in formulating treatment; where the drug would only attack disease-causing microorganisms without harming other cells.

After testing compound “606” in more animals, Ehrlich and Hata went on to conduct successful human trials of the chemical. While the treatment still had toxic side-effects, it was made available under the name Salvarsan. Salvarsan, and later its less harmful derivative Neosalvarsan, became a popular treatment for syphilis. Among the first physicians to administer Salvarsan in London was a young Alexander Fleming, who doled it out to rich patients at his small private practice.

When World War I broke out in 1914, Fleming found himself at a special battlefield hospital alongside his colleagues from the St Mary’s Hospital Medical School’s bacteriology lab. Watching soldiers succumb to simple infections gone wrong, Fleming realised the antiseptics used for these wounds did more harm than good. He wondered if there were a substance, like the chemical in Salvarsan, which could kill off bacterial infection in wounds.

The not-so-accidental find

Returning to his lab after the war, Fleming continued to look for the perfect antiseptic. Although he discovered that lysozyme, an enzyme found in bodily fluids like saliva and tears, had a mild antibacterial effect, it was a few more years before his legendary discovery.

Fleming had so much going on in his lab that it was often in a jumble. In fact, he was so comfortable with mould and bacteria that he used them outside the lab as well: for painting. According to Smithsonian magazine, Fleming upgraded from watercolours to bacteria in the artistic pursuits of his leisure hours, using a paint-by-numbers approach to landscapes and still life by “growing microbes with different natural pigments in the places where he wanted different colours.

“A less observant scientist, or one more fussy about keeping a tidy laboratory, would have thrown out the adulterated growth,” TIME magazine noted in its 1944 profile of Fleming, referring to his forgotten and contaminated Petri dish in the sink. Fleming noticed that the bacteria in proximity to the mould colonies were dying, as evidenced by the dissolving and clearing of the surrounding agar gel. He also found that it was not the mould itself but rather its ‘juice’ that killed bacteria. He named the “mould juice” penicillin.

Although Fleming published the discovery of penicillin in the British Journal of Experimental Pathology in 1929, the paper drew little attention form the scientific fratenity. Additionally, Fleming found it difficult to isolate his “mould juice” in large quantities. It took World War II to revitalise interest in penicillin, with scientists Howard Florey and Ernst Chain leading the calvary for treatment against infections.

A team effort

Florey, the director of the William Dunn School, came across Fleming’s paper on the penicillium mould in 1938. Soon after, he and his colleagues teamed up to unravel the science beneath what Fleming called penicillium’s “antibacterial action.”

Florey’s team was a heady mix for the era: an international multi-disciplinary team of quirky scientists that is an enduring example of how drug development needs brilliant minds across cultures. Florey himself was an Australian, while his chemist Ernst Boris Chain was a German Jewish immigrant; the rest of the team had a significant portion of researchers from other countries and refugee backgrounds.

It is equally important to note that the team was not all-male either. Women scientists like X-ray crystallographer Dorothy Crowfoot Hodgkin were instrumental in making penicillin a reality. There were also the famous “penicillin girls”, women as young as 16, who did the hard work of culturing the Penicillium mould in the Dunn School’s basement – working through nights as a war raged outside, and risking developing penicillin allergies themselves.

In February 1941, the team started its first human trials: several patients with a yellowish-brownish solution containing penicillin. It was a painful experience for the patients, due to the size of the needles and impurities, with some describing it has having “boiling water” injected into their bottoms. The results of the treatment were, however, miraculous. Within days, doctors reported startling recoveries of patients suffering from life-threatening bacterial infections.

The successful conclusion of the clinical trials convinced Allied decision-makers to support further penicillin work. By the end of the same year, penicillin had been taken to the United States, where additional research resulted in a dramatic upscaling of drug production.

These initial studies set the path for other researchers to uncover more antibiotics that made their way to the patient’s bedside. The period between the 1950s and 1970s in particular, was heralded as the golden era of discovery of novel antibiotics — especially as there have been no new types discovered since then. All in all, it definitely took a little more than a mouldy dish.

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