On Monday 3 September 1928, Alexander Fleming saw something that would later revolutionise modern medicine and save countless lives. His finding opened the way to treating deadly infectious diseases and enabled the development of surgery, organ transplantation and cancer chemotherapy. He discovered penicillin.
It’s often described as an accidental discovery, yet Fleming could have easily overlooked what he saw that day. Natural curiosity together with astute observation form the foundation of scientific enquiry. To some degree in science you make your own luck. So chance observation or moment of genius?
That Fleming was a researcher at all, was serendipitous. You could describe him as an accidental researcher. He had planned to train as a surgeon when he graduated with a medical degree from St Mary’s Hospital in London in 1908. Two years earlier, while he was still studying, Fleming was persuaded to take a temporary job as a junior research assistant by fellow doctor, John Freeman. Freeman was an enthusiastic member of St Mary’s Rifle Club, which needed some new talent for various shooting competitions. Fleming, as it happened, was a brilliant marksman, and Freeman was keen to find reasons for him to stay. In fact, Fleming remained a member of the Inoculation Department at St Mary’s Hospital for the next 49 years.
The Day that Changed the World
Imagine the scene. Fleming had returned to work at St Mary’s Hospital Medical School after a summer holiday with his family at their country home in Suffolk. The newly promoted Professor of Bacteriology sat at his cluttered laboratory bench and began to sort through a stack of petri dishes (culture plates) containing cultures of a common bacterium known as Staphylococcus aureus. Fleming would often leave petri dishes containing cultures on his bench for several weeks to see what happened to them. Not surprisingly, he found a number of petri dishes were contaminated with yeasts and moulds. Then a visitor arrived at the laboratory.
Martin Pryce had been Fleming’s research assistant until earlier that year when he took a position as a pathologist, also at St Mary’s. While the two men were chatting, Fleming noticed something unusual on one of the petri dishes. “That’s funny,” he said as he handed it to Pryce. They observed numerous colonies of bacteria growing as distinct blobs on agar jelly at one end of the dish and two large colonies of contaminating mould at the other. However, the bacteria colonies were smaller and more sparse the closer they were to the fungus, as if it had secreted a substance that prevented bacterial growth. Fleming took a sample of the mould to culture it further, photographed the petri dish and then preserved it in formalin vapour. Incredibly, the same petri dish can be found in the British Library today. Rather crisp and dried up by all accounts but a remarkable piece of medical history nonetheless.
At this point in the story it would be nice to say “the rest is history”, only of course it’s not that simple. Over the next few months, Fleming further investigated the mould and the anti-bacterial substance it produced. Fungus expert Charles La Touche, who worked in a laboratory downstairs, identified the mould as a member of the Penicillium family. The active ingredient in the “mould juice” was unstable and difficult to work with. However, crude material derived from the mould culture killed several types of harmful bacteria. Fleming named the active ingredient penicillin and published his findings in the British Journal of Experimental Pathology in June 1929 to little critical acclaim. He proposed penicillin could be used as an antiseptic and for isolating certain bacteria from culture mixtures, given not all bacteria were destroyed by it. Hardly a soul in the scientific community appeared to notice except for a few bacteriologists who saw penicillin as a useful tool.
Oxford takes up the Baton 10 Years Later
As war broke out in 1939, a multidisciplinary team led by Australian pathologist Howard Florey and Ernst Chain at the Sir William Dunn School of Pathology in Oxford were working on the purification and chemistry of penicillin. Florey was undeterred by the difficulties of working with penicillin and had an eye for research that could deliver.
Penicillium mould was grown in whatever vessels the group could get their hands on – bedpans, food tins, milk churns. “Penicillin girls” were employed at £2 per week to oversee the fermentation process. Biochemist Norman Heatley devised a method to extract penicillin from large culture volumes. Another biochemist, Edward Abraham, used a then new technique (alumina column chromatography) to remove impurities.
On 24th August 1940, as London reeled in the aftermath of an all-night bombing raid that began the Blitz, Chain, Florey and colleagues published an article in The Lancet titled “Penicillin as a chemotherapeutic agent”. Their research showed penicillin had a therapeutic effect and had protected mice from three types of bacteria. They concluded “it would seem a reasonable hope that all organisms inhibited in high dilution in vitro (in a laboratory) will be found to be dealt with in vivo (in living things)”.
War Years Collaboration
Clearly, penicillin showed much promise but substantial amounts would be needed for clinical trials and subsequent therapeutic use if the trials were successful. Florey and Heatley travelled to the USA in the summer of 1941 to find help.
Over the next few years, an enormous Anglo-American effort to expedite penicillin production followed, including a collaborative program between US Government agencies and the pharmaceutical industry. A better penicillin-producing strain of mould was identified and growing conditions were optimised to increase the yield of the drug. Clinical studies confirmed the therapeutic use of penicillin in treating streptococcal, staphylococcal and gonococcal infections, as well as syphilis.
By the autumn of 1943, doctors were treating American and Allied military in combat zones with penicillin to prevent wound infections. There was limited access to the antibiotic for civilians with life-threatening infections. More than 20 companies worked day and night, and by 1945 manufacturing techniques were producing an 80-90% yield of penicillin in 10,000 gallon tanks. Thousands of Allied troops benefited from penicillin treatment between D-Day and the final German surrender in May 1945.
The Nobel Prize in Physiology or Medicine 1945 “for the discovery of penicillin and its curative effect in various infectious diseases” was awarded jointly to Alexander Fleming, Ernst Chain and Howard Florey. Alexander Fleming and Howard Florey received a knighthood from King George VI in 1944.
The Antibiotics Era Begins
Other antibiotics were discovered in soil bacteria: streptomycin (1943), cephalosporins (1945), chloramphenicol (1947) and tetracyclines (1948). A class of antibiotics known as quinolones was discovered accidentally as a result of research on the anti-malarial drug chloroquine in 1962, and made synthetically by chemists. In the 1970s and 1980s synthetic versions of erythromycin were developed.
Fake Fact Alert
For the record, Fleming never said: “When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I suppose that was exactly what I did.” You’ll find this “quote” all over the Internet. For starters the date is wrong. It appears to be from a popular American science book, and according to Fleming’s biographer Kevin Brown “it is certainly not in Fleming’s style, and the phraseology is North American.”
The Use and Abuse of Antibiotics
Fleming warned of the dangers of bacterial resistance in his Nobel Lecture in December 1945. He observed “it is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them.” He advised “if you use penicillin, use enough.”
Fast forward to today, antimicrobial resistance, which includes antibiotic resistance, is an emerging global health threat with a dramatic increase in harmful bacteria unaffected by multiple antibacterial agents. Antibiotic resistance is a natural phenomenon in harmless soil bacteria to help deal with biological threats. However, underuse, excessive use and misuse of antibiotics by humans has created drug-resistant strains of harmful bacteria (not usually resistant to antibiotics) known as superbugs. It’s a classic example of Darwin’s selection and survival in action and has unfolded into an arms race between microbes and man. Exposure to antibiotics provides the selective pressure for the rise and spread of resistant pathogens. If things don’t change, the microbes may win. A post-antibiotic era could become a reality.
Huge amounts of antibiotics have been used to promote growth as well as prevent and treat infections in farm animals. Antimicrobial agents accumulate through sewage, manure and water bodies in the environment, making it a breeding ground for microbes that are resistant to antibiotics, biocides, disinfectants and detergents. Antibiotics have frequently been prescribed to treat relatively benign illnesses in humans. The Centers for Disease Control and Prevention (CDC) in the USA suggest antibiotics are not optimally prescribed up to 50% of the time, often when not needed. There is also incorrect dosing and duration of treatments.
Almost 50,000 people in the USA and Europe die each year as a result of antibiotic-resistant infections. Treatment of patients infected with drug-resistant pathogens is expensive as a result of costly last resort drugs and longer hospitalisation. The annual economic burden associated with treating antibiotic-resistant infections is between $21,000 and $34,000 million in the USA and €1500 million in Europe.
Bacteria become resistant to antibiotics via mutations in their genes or by hijacking mobile genetic elements carrying resistance genes from each other. They have several strategies for resisting antibiotics.
- They inactivate the antibiotic using enzymes, a process called enzymatic degradation.
- They alter or produce more of the molecule the antibiotic targets.
- They keep the antibiotic out by a) reducing the porousness of their cell membrane or b) by pumping it out via a process called efflux.
Can we Combat Antimicrobial Resistance?
A grim scenario predicts as many as ten million deaths per year by 2050 and rising healthcare costs. The poorest countries will be affected the most given their high antibiotic consumption to treat infections resulting from inadequate sanitary conditions. Substandard and counterfeit drugs, unregulated dispensing together with short-term dosing because of costs all combine to make poverty a major driving force for antibiotic resistance.
Coordinated action on a global scale from Governments, policy makers, public health authorities, academic institutions, agricultural and pharmaceutical companies will be vital to bringing antimicrobial resistance under control. Many countries have formed national action plans on antimicrobial resistance to reduce antibiotic consumption. The Global Action Plan on Antimicrobial Resistance endorsed by the member states of the World Health Organization in 2015 has the following goals:
- to improve awareness and understanding of antimicrobial resistance
- to strengthen knowledge through surveillance and research
- to reduce the incidence of infection
- to optimise the use of antimicrobial agents; and
- develop the economic case for sustainable investment that takes account of the needs of all countries, and increase investment in new medicines, diagnostic tools, vaccines and other interventions.
There are a number of ways to tackle antibiotic resistance.
1. Prevent infections in the first place
Immunisation, safe food preparation and hand washing can prevent infectious diseases from spreading. Healthcare facilities should have infection-control guidelines that include hand hygiene before and after patient interactions to reduce the risk of transmitting pathogens.
2. Improve surveillance of antibiotic resistant infections
There is a need to improve tracking of antibiotic use and resistance data globally. Systematic collection of data in health and farming would help to create a more complete picture of the current situation and emerging threats. Organisations such as the CDC, the European Centre for Disease Prevention and Control (ECDC) and some pharmaceutical companies track data on antibiotic resistant infections.
3. Reduce environmental releases of antibiotics and antibiotic resistant bacteria
Environmental exposure can be reduced by treatment of wastewater from cities, pharmaceutical manufacturing sites and hospitals. Treatment strategies have yet to be perfected and further research is needed to improve existing approaches or find new ones.
4. Develop new diagnostic tests
New diagnostics that can rapidly identify bacterial infections are needed to provide appropriate therapy faster and reduce the need for broad-spectrum drugs. Identifying infections is often based on observation rather than specific testing. General Practitioners may prescribe successive courses of antibiotics until an effective treatment is found for example. Historically, testing has taken several days using traditional methods that look at things like how the microbes grow in certain media and the appearance of the colonies they make. However, faster molecular techniques are now available and require further investigation and implementation.
5. Improve antibiotic stewardship / prescribing
Antimicrobial resistance can be reduced through antibiotic stewardship programs which guide prescribers in administering antibiotics properly. The use of antibiotics only when needed in animals and humans with the right medication at the appropriate dose and duration can result in significant cost savings as well. Some studies show shorter patient stays and lower inhospital mortality due to good stewardship. However, research has found educational programs have not been effective in reducing the overall overuse of antibiotics.
6. Develop new drugs / approaches to treating infections
More research into the discovery and development of new antibiotics is needed. As awareness of antibiotic resistance has increased, the pharmaceutical industry has returned to more antibiotic discovery and development programs. There was a decline in industry investment over a decade for several reasons. Antibiotics are less profitable than other drugs because they are only used for a relatively short period of time compared to medications for chronic conditions. New antibiotics tend to be held back as a “last resort” to combat serious illnesses only when older agents have failed which means they don’t get used so much. In addition, how quickly microbes will develop resistance to a new drug is unpredictable… a huge investment into drug development could be lost in a short space of time. Regulatory barriers have been another issue with problems including differences in clinical trial requirements among countries and changes in regulatory and licensing rules.
The Access to Medicine Foundation published “The Antimicrobial Resistance Benchmark” in 2018 to rank company efforts in combating antimicrobial
resistance. The independent report compared 30 companies and found GlaxoSmithKline followed by Johnson & Johnson were doing the most. Key findings were as follows:
- There are 28 antibiotics to treat high-priority pathogens in the late stages of development.
- Almost half the companies evaluated are involved in efforts to track patterns in antibiotic drug resistance, with antimicrobial resistance surveillance programmes running in 147 countries.
- Eight companies are setting limits on the levels of antibiotics that can be released into the environment in wastewaters at their antibiotic manufacturing facilities although what is released in practice is not published.
- Four companies are taking steps to separate sales agents’ bonuses from the volume of antibiotics they sell.
Research groups around the world continue to investigate drug discovery and resistance mechanisms. Some research is looking at how to deploy our current arsenal of antibiotics more effectively. Advances in technology have improved the ability to make new compounds and screen for activity. New sources of antibiotics are sought among marine bacteria, tropical rainforests, soil and from extreme environments. Other work is investigating ways of immobilising pathogens without killing them and new targets are being tested such as genes critical to pathogenic survival. Researchers hope against hope these studies will generate new compounds or approaches. One thing’s for sure, antimicrobial resistance will continue to evolve. It’s the nature of the beast.
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If you’re in London, a visit to the Alexander Fleming Laboratory Museum is well worth a visit. It’s open to the public Mondays to Thursdays between 10 am and 1 pm.
On the anti-bacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae The British Journal of Experimental Pathology (1929)
Nobel lecture, December 11 1945 Alexander Fleming
Discovery and Development of Penicillin American Chemical Society
The Antibiotic Resistance Crisis Part 1: Causes and Threats Pharmacy and Therapeutics (2015)
The Antibiotic Resistance Crisis Part 2: Management Strategies and New Agents Pharmacy and Therapeutics (2015)
Antimicrobial Resistance Benchmark 2018 Access to Medicine Foundation
Global Action Plan on Antimicrobial Resistance (2015) World Health Organization
Strategies to combat antibiotic resistance in the wastewater treatment plants Frontiers in Microbiology (2017)
About Antimicrobial Resistance Centers for Disease Control and Prevention
Great video on how bacteria resist antibiotics The Longitude Prize