From riches to bust: How antibiotic resistance developed in the modern world

We went from a flurry of new antibiotics in the mid-20th century, to almost none in the 21st century. So what happened?

In 1967, the US surgeon general of the time, William Stewart, was quoted as saying: “The time has come to close the book on infectious diseases. We have basically wiped out infection in the US.”

Although, since that time, the quote has proven to have grown out of an urban legend. The sentiment falsely attributed to Stewart unfortunately mirrors a time when it seemed there was no stopping scientific progress in developing new antibiotics.

Yet here we are, decades later, and the World Health Organisation (WHO) has recently issued not one but two pleas for the development of new antibiotics as more and more strains of infections such as tuberculosis (TB) become more resistant to treatment.

In the space of 70 years, in fact, effective antibiotic research has basically ground to a halt, with just two new drugs for the treatment of TB being developed.

This is despite the fact that 250,000 people die each year from the strains immune to antibiotics, with the number expected to grow.

Finally, just to drive home the stark realities of a world where antibiotics are no longer effective, even minor surgeries or infection would be untreatable, setting decades of scientific progress back to before the industrial age.

So, the question is: how did we get here and why are multibillion-dollar pharmaceutical companies not producing any more?

From accidental discovery, to an accident waiting to happen

The discovery of penicillin dates back to 1928 when Alexander Fleming famously stumbled upon its healing properties after he accidentally left a petri dish next to an open window, though it wasn’t until 1945 that the secret of mass producing it was revealed.

By using x-ray crystallography, renowned chemist Dorothy Crowfoot Hodgkin was able to determine the chemical structure of penicillin and thus, how to manufacture it en masse. This later won her the Nobel Prize for Chemistry in 1964.

To get an understanding of how little penicillin there was in that intervening period, pharma giant Merck used half of the US’s total supply on a patient with streptococcal septicaemia in 1941.

Thanks to Hodgkin’s enormous breakthrough, once-small pharma companies exploded in size as the world entered the golden age of antibiotic discoveries in the 1950s and 1960s, promising miracle cures for common ailments.

Hodgkin’s atomic structure of penicillin using x-ray crystallography. Image: Science Museum London/Science and Society Picture Library (CC BY-SA 2.0)

In 1944, the antibiotic streptomycin was developed by Albert Schatz and Selman Waksman and was released on the market, again by Merck, just two years later – a timeline that would be unthinkable today.

At that time, the pharma companies only saw massive profits when it came to their production so, as research into finding new antibiotics was considerable, so too was the marketing.

Incredibly, companies such as Candette began selling orange-flavoured antibiotic cough drops as a cure for a sore throat in the 1950s, something that would be deemed a complete waste in the modern era.

Behind the optimism summed up in the fake William Stewart quote, researchers not particularly interested in financial gains began to raise warning flags that the good times might not necessarily roll forever.

A stark premonition

In his speech accepting the Nobel Prize in 1945, before the golden era had even started, Fleming issued an eerily prophetic warning.

“The time may come when penicillin can be bought by anyone in the shops,” he said.

“Then there is the danger that the ignorant man may easily underdose himself and, by exposing his microbes to non-lethal quantities of the drug, make them resistant … If you use penicillin, use enough.”

Not long after Fleming’s speech, the WHO held meetings to discuss the possibility of resistance occurring from overuse, but these fizzled out due to heated debates over definitions and hypotheticals.

During this time, the agricultural sector decided animals could also benefit from the use of antibiotics. To prevent animals developing infections that could hurt their profits, food producers began pumping animal feed full of various antibiotics.

In Asia alone, the daily intake of animal protein has more than quadrupled since 1960 and 105,500 tonnes of drugs are expected to be used in animal feed by 2030 – a shocking figure that has contributed greatly to today’s predicament.

‘We took our eye off it in the developed world when things started to improve but, of course, now it is coming back to bite us’
^{– PROF STEPHEN GORDON}

Speaking with Siliconrepublic.com, associate dean for research, innovation and impact at University College Dublin’s School of Veterinary Medicine, Prof Stephen Gordon, said that the decline in antibiotic production began in the 1970s.

After the “low-hanging fruit” was picked early by the pharma giants, the profit margins for creating new ones fell sharply and funding for drug research went into other areas.

“They were a victim of their own success,” Gordon said. “Companies are driven by profit and it’s more profitable to develop a drug that someone needs to take for years, instead of an antibiotic that will last 10 days.”

Add to that the cockiness that arose in the developed world where, as Gordon has seen first-hand from his own research, infections such as TB are considered to be far removed from the average person, even though it remains a massive global killer in less-developed nations.

“We took our eye off it in the developed world when things started to improve but, of course, now it’s coming back to bite us with antimicrobial resistance,” Gordon added.

So, how do we answer the WHO’s plea for more antibiotics when funding remains relatively low and, as said earlier, only two new drugs for one type of infection have been produced in more than half a century?

The answer is twofold, according to Gordon, who thinks that while significantly more funding needs to be put into research – whether that is directly through pharma companies or through public-private partnerships – we also need to look in places where we might not expect.

Could sea sponge harbour a silver bullet for antimicrobials? Image: Sarnl/Shutterstock

Finding answers under the sea

“In the [golden era of discovery] it was largely soil bacteria and soil fungi that were mined to identify different antibiotics,” Gordon said. “But what we need to do now is really revisit the development of antibiotics and the identification of new compounds to really move things forward.”

One such place is at the bottom of the ocean, where vast, vast tracts remain unexplored by humans.

In recent years, deep-sea sponges have been identified as having potential antimicrobial properties within their microbiome. A team of scientists from University of Plymouth has cultured more than 100 novel bacterial strains from them.

But, away from the finger-pointing of how we got here and the actual production of antibiotics, scientists enmeshed within this field are telling us we have to be smarter about how we use them.

Even if we were to create a couple of new antibiotics every year, it will mean nothing if we continue down the same path of pumping them into our bodies and our food production lines, with little regard for the long-term effects.

We have changed our worldview on climate change after its onset became more and more apparent, so why can’t we do the same with antibiotic resistance?

Only time will tell.