80 years of antibiotics: our greatest medical breakthrough and the threat to its future
The course of medicine changed eighty years ago...
In 1945, penicillin antibiotics became widely available to the public for the first time. Before their discovery and development, common infections had devastating consequences, and many were untreatable.
But today, disease-causing bacteria have evolved to resist the action of these medicines. Due to antimicrobial resistance (AMR), common illnesses such as urinary tract infections, sexually transmitted infections and pneumonia are once again often becoming untreatable.
A brief history of penicillin antibiotics
Scroll to learn about 80 years of antibiotic discoveries, or use the button to skip ahead to the article
1928
Alexander Fleming first observes that Penicillium mould prevents the growth of certain bacteria on a petri dish.
1939
Howard Florey, Ernst Chain, Norman Heatley, and others begin investigating penicillin further, finding ways purify it into a useful antibiotic, and to produce it on a large scale.
1941
Penicillin is used to treat a human patient, a police officer named Albert Alexander, for the first time.
1939-45
A partnership between scientists, government and the pharmaceutical industry in the US leads to mass-production of antibiotics for soldiers in world war two, saving thousands of lives.
1945
Chain, Florey and Fleming are jointly awarded the Nobel prize in Physiology and Medicine. In his acceptance speech, Alexander Fleming warns of the ‘dangers of overusing’ antibiotics.
1946
Dorothy Crowfoot Hodgkin confirms the structure of penicillin with a technique called X-ray crystallography, a structure first proposed by Edward Abraham.
Early 1940’s to mid-1960’s
An era of rapid discovery, during which almost all our current antibiotic classes were created, leads researchers into the ‘Golden Age of antibiotics’.
1980’s
The golden age cannot last forever, and the pipeline of antibiotic discovery begins to dry up. In the decades since, far fewer new classes of antibiotics have made it to clinical trials, let alone human use.
Present day
In 2023, 1 in 6 common bacterial infections were resistant to at least one of the major classes of antibiotics.
With bacteria becoming increasingly resistant to antibiotics, it’s more important than ever to protect the drugs we have, and to pioneer new research to find more treatments and therapies.
Without urgent action, antimicrobial resistance is predicted to cause:
39 Million Deaths
With up to 90% occurring in Africa or Asia
$100 Trillion
In losses to the world economy
At the Ineos Oxford Institute for antimicrobial research (IOI), world-class research is ongoing to investigate the nature of AMR, and to develop innovative new treatments.
Building on decades of research, our scientists are working to develop for new antibiotics, and searching for new ways to protect existing antibiotics from AMR.
Penicillin exploits a powerful ring
The penicillin story is well known – Fleming's chance encounter with a mould on his bacterial sample makes for a compelling tale. However, as with most great discoveries it took the hard work and collaboration of many researchers to take Fleming’s original findings, and turn them into a workable antibiotic drug - one that could be produced and used on a massive scale.
In 1941, the first ever patient was treated using penicillin, but scientists were only certain of penicillin’s structure around five years later, which allowed them to find out.
Revealing this structure took the hard work of Oxford chemist and Nobel prize winner Dorothy Hodgkin, who used X-ray crystallography to study penicillin on a molecular level. For the first time, she clearly defined the structure that had first been proposed by Edward Abraham, another Oxford chemist.
Their research revealed that penicillin’s power lies in a tiny chemical structure at the core of the compound called a β-lactam ring. Today, an entire class of penicillin-like antibiotics rely on this central ring for their bacteria-killing strength.
“Penicillin and related antibiotics use a β-lactam ring to prevent bacteria from dividing, by blocking their ability to build new cell walls. They latch onto their targets by binding onto specific enzymes, called ‘Penicillin Binding Proteins’, which are not present in humans - allowing them to kill bacteria without affecting human cells.”
- Dr Alistair Farley, IOI Scientific Lead, Drug Discovery -
Penicillins, and related β-lactam drugs, are the most globally prescribed class of antibiotic, cementing their discovery and development as one of our biggest medical breakthroughs. But resistant bacteria threaten to undermine their utility, potentially dragging us back into a pre-antibiotic era.
Bacteria fight back with ring destroying enzymes
Bacteria can very rapidly adapt to survive the threats antibiotics pose to them. In some cases, they develop methods to pump drugs out of their cells, and they can also develop tough outer layers to make it harder for drugs to get in.
But when it comes to fighting off penicillin-like drugs, bacteria have a range of more powerful counterattacks.
To neutralise β-lactam antibiotics before they can latch onto their targets, bacteria produce ring destroying enzymes called β-lactamases. These powerful enzymes - some of which evolved from penicillin binding proteins - destroy the β-lactam ring inside the drug before it can bind to its target in the bacteria, rendering the antibiotic ineffective.
Scientists have found ways to overcome this resistance by developing drugs that can neutralise these enzymes, creating 'guardian’ compounds that protect our antibiotics from attack.
Guardian drugs do this by targeting the ‘active site’ of the β-lactamase - a uniquely shaped region of the enzyme that is essential to its function. To defend against these enzymes, guardian compounds need to be a near-perfect mirror image of this shape. Then, like a puzzle piece slotting into exactly the right place, they can sit just inside the active site and prevent the enzyme from binding to any antibiotics.
"Antibiotic guardian molecules block the active site of β-lactamases, allowing their partner antibiotic to carry out its function and restoring the utility of penicillin drugs to fight infections."
- Prof Chris Schofield, IOI Director of Chemistry
Clavulanic Acid: the first antibiotic guardian
Fifty years ago in the UK, Beecham Research Laboratories reported on the first ever guardian molecule for penicillin, known as clavulanic acid, which had been isolated from bacteria in the lab.
Ten years later, it was approved for used in partnership with with the β-lactam antibiotic amoxicillin, and branded as 'Augmentin'.
Part of the original Beechams laboratory, credit: Koncorde at English Wikipedia
Part of the original Beechams laboratory, credit: Koncorde at English Wikipedia
Still widely used today, Augmentin was a pioneering breakthrough in the history of antibiotics. However, bacteria have fought back by producing β-lactamases that can counteract even clavulanic acid, which researchers are countering in turn with all-new types of antibiotic guardians.
“Without antibiotic guardians like clavulanic acid, many common infections would be much more difficult to treat. But b-lactamases are getting better – to combat antimicrobial resistance we need to both adapt our arsenal of guardians and develop completely new antibiotics.”
- Dr Liam Wilson, Postdoctoral Research Associate at the IOI -
Often used in combination with existing antibiotics, guardians are powerful tools to enhance the effects of their partner antibiotics. Researchers call these ‘combination therapies’, which refer to treatments that make use of use multiple drugs for better results.
Today, IOI researchers are developing new antibiotic guardians and combination therapies to tackle the rising threat of AMR.
Finding new antibiotics
At the IOI, researchers like Dr Helen Smith are finding new ways to outsmart bacterial resistance. Using a technique called X-ray crystallography, an advanced version of the methods pioneered by Dorothy Hodgkin and others, they can study the structure of the bacterial targets of β-lactams, and the resistance enabling β-lactamases, atom by atom.
"Our work centres on gaining a deeper understanding of how new antibiotics bind to their bacterial targets. The more we learn about how β-lactams interact with their target enzymes and β-lactamases, the better prepared we are to develop new treatments which may overcome antimicrobial resistance.”
- Dr Helen Smith, Postdoctoral Research Associate at the IOI -
To see the structure of bacterial enzymes in atomic detail, the researchers mix samples of purified proteins with different chemicals. Over time these allow formation of small crystals of the protein that can be ‘fished’ out with microscopic loops.
These crystals are then sent to Diamond Light Source in Oxfordshire, where a powerful beam of X-rays is fired through the crystals to allow researchers to solve their structure.
When projected through crystals, X-ray beams are scattered by the atoms within forming ‘diffraction patterns’ of dark and bright spots that can be measured by scientists. Scientists interpret these patterns like a bar-code, full of information about how the molecules inside the crystal are arranged.
Armed with a better understanding of the enzyme’s 3D structure, the researchers can then start to predict how new compounds may interact with its active site. This helps them to judge whether a new potential inhibitor compound will be the perfect puzzle piece, binding to the enzyme more tightly than existing guardian compounds, demonstrating potential as a new antibiotic.
The Diamond Light Source Synchrotron in Oxford
The Diamond Light Source Synchrotron in Oxford
The Diamond Light Source Synchrotron in Oxford
The Diamond Light Source Synchrotron in Oxford
A 3D model of the structure of an enzyme
A 3D model of the structure of an enzyme
Beyond two-drug treatments
While antibiotic-inhibitor combinations make a powerful pair, bacteria will always continue adapting. IOI researchers are testing combination therapies that involve three different drugs, with an additional inhibitor opening new possibilities for defending antibiotics.
These therapies are more effective because the β-lactamase enzymes that attack antibiotics come in two different forms; metallo-β-lactamases (MBLs), and serine-β-lactamases (SBLs). Most inhibitors, including clavulanic acid, focus only on SBLs, leaving antibiotics open to attack from the other form of enzyme. At the IOI, researchers are developing new MBL inhibitors, which can fill this gap in the antibiotic’s defence.
So far, tests have shown that using both inhibitors makes for a more effective combination therapy than only one. By combatting different pathways of resistance at once, researchers are showing there are still new ways to extend the lives of our antibiotics, securing the future of penicillin’s family of drugs.
“The UK has a long history of antibiotic innovation, and now the IOI is raising the flag for AMR research. For too long, the field has suffered from underinvestment. We, our partners, and others are working to develop new classes of antibiotics, inhibitors, and combination therapies to combat the growing threat of AMR.”
- Prof Christopher Schofield, IOI Director of Chemistry -
Ineos Oxford Institute for antimicrobial research (IOI)
To learn more about our multifaceted approach to studying and providing solutions to antimicrobial resistance, you can read our latest news and publications on the IOI website, and by following us on social media.
Built with Shorthand