The narrative of penicillin’s discovery has been polished to a Hollywood sheen. Imagine a world where a simple scrape on the knee still meant a death sentence and where pneumonia or puerperal fever were whispered about in horrifying tones. That world was a morbid reality in the early twentieth century until a fortuitously mouldy lab bench changed everything. Sir Alexander Fleming’s serendipitous discovery of penicillin in 1928 did far more than win him a Nobel Prize. It inaugurated the antibiotic era and has been saving countless millions of lives. But the true story is far messier, ethically fraught and scientifically complex than the legend suggests. For over a decade, penicillin languished in obscurity, itis potential ignored even by it’s discoverer. As historian Lord Robert Winston noted…

"Fleming didn’t save the world—he almost threw it away!"

On a drizzly September morning in 1928, a dishevelled Scottish bacteriologist returned to his chaotic laboratory at St Mary’s Hospital, London after a holiday in Suffolk. The London drizzle had seeped into the laboratory walls and left a damp chill in the air. What Alexander Fleming found on a discarded petri dish would ignite a medical revolution and it began with his grumbling about messy lab assistants. He sorted through petri dishes abandoned by his assistant. One dish was contaminated with a Penicillium mould which displayed a phenomenon that would alter human history. It was dotted with bacterial colonies except around a Penicillium mould where a clear zone indicated that the fungus was secreting a powerful antibacterial agent. Fleming’s muttered observation – “That’s funny!” — was perhaps the greatest understatement in medical science.

“When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionise all medicine by discovering the world’s first antibiotic... But I suppose that was exactly what I did”.

Let us journey through Fleming’s life, the evolution of penicillin production, it’s modern challenges and the cutting‐edge research striving to keep this 'miracle drug' one step ahead of the microbes that would defeat it. This is the story of what happened between the accident and the apotheosis — and also why it matters in our age of superbugs.

Quick history

In the interwar years, the young physician Alexander Fleming could never have anticipated that a stray mould would transform human health. In September 1928 he returned from holiday to find one of his staphylococcus Petri dishes. As Fleming later quipped, that September morning he…

“…certainly didn’t plan to revolutionise all medicine by discovering the world’s first antibiotic”.

He even noted dry-eyed in his notebooks that Penicillium’s antimicrobial effect could isolate one bacterium from another. This chance event (aided perhaps by an open-window draft carrying Penicillium spores into his lab) set the stage for the ‘miracle drug’ era. Fleming initially called the unknown substance simply ‘mould juice’ and he studied it as a laboratory tool more than a medicine. Fleming did not inject his new extract into infected animals or patients but he believed cures 'come from within' the body. So, he regarded it primarily as a bacterial sorter and topical antiseptic.

It took the later work of Ernst Chain, Howard Florey and Norman Heatley at Oxford to show that Fleming’s serendipitous find was a true therapeutic breakthrough. They famously scaled up production using bathtubs and milk churns and then enlisting a team of part‑time ‘penicillin girls’ to grow mould in bedpans and churns. Their persistence paid off. By the year 1940, Oxford mice were being cured of deadly infections and even a deeply ill policeman (PC Albert Alexander) briefly recovered under penicillin therapy before doses ran out.

The unlikely hero

Born on 6 August 1881 in a remote farm at Darvel (Ayrshire, UK) young Alexander Fleming was the third of four children in a farming family. Early chores among cows and soil instilled in him a keen eye for detail and unshakeable resourcefulness. Against his parents’ wishes (who hoped he would stay on the family farm), Fleming pursued medicine, won a scholarship to Kilmarnock Academy and later enrolled at St Mary’s Hospital Medical School in London in the year 1903. In those pre‐antibiotic days, antiseptics were applied liberally to wounds, which was often inflicting more harm than healing.

Alexander Fleming’s path to immortality began with a dead uncle’s inheritance and sheer luck. His father Hugh Fleming died when Alexander was just seven that left the family in financial uncertainty. After working as a London shipping clerk for four years, a £250 inheritance (about £30,000 today) from his uncle allowed him to enrol at St Mary’s Hospital Medical School in the year 1901. Fleming’s career nearly took a different turn entirely. A champion sharpshooter with the London Scottish Regiment, his rifle club captain famously intervened…

“Wait! Don’t become a surgeon – join our research department instead! We need good marksmen!”

The bacteriologist Sir Almroth Wright

Thus began Fleming’s apprenticeship under Sir Almroth Wright who was a pioneer in vaccine therapy. Their wartime experiences in Boulogne’s battlefield hospitals would shape Fleming’s destiny. Fleming witnessed First World War casualties arriving with infected shrapnel wounds who were ‘scrubbed till they bled’ and then only to succumb to gangrene or septicaemia. The experience sharpened his conviction that nature might hold gentler and more effective weapons against infection. Horrified by soldiers dying from infected wounds despite antiseptic treatment, he made a crucial observation…

“Carbolic acid kills white blood cells faster than bacteria! We’re sacrificing the defenders to attack the invaders!”

This insight foreshadowed his revolutionary approach to infection and his search for targeted antibacterial agents.

Forgotten antecedents and unlikely precursors

By revisiting ancient remedies, we can find that Egyptian papyri (c. 1500 BCE) describe poultices of mouldy bread for ulcers. Though empirical, these treatments vanished until Fleming’s serendipity resurrected their principle.

Egyptian papyri mentioning treatment using mouldy bread

Early observations from 19th‑century botanist Cassie Lister noted Penicillium suppressing bacterial cultures in 1871 yet it lacked Fleming’s curiosity to pursue it.

Before the penicillin breakthrough, Fleming’s ingenuity led to the discovery of lysozyme in the year 1921. He traced this to a natural enzyme in nasal secretions and tears that could dissolve bacterial cell walls. Though mild compared to antibiotics, lysozyme hinted at the potential of naturally occurring antimicrobials. Though medically limited, this taught Fleming to spot bacterial inhibition. When he saw the mould’s effect in 1928, he reportedly quipped to colleagues…

“That’s funny...these mould colonies seem to be dissolving the staphylococci!”

He named the mysterious substance 'penicillin' and published his findings in the year 1929. But the scientific response was glacial. As Fleming noted dryly…

“I’ve been trying to point out the advantages of penicillin but get little support”.

The birth of Penicillin

When he left for Suffolk on August 28 (1928), he stacked several Staphylococcus culture plates near an open window. The temperature dip to 15°C favoured mould growth while the subsequent warmth to 25°C allowed bacterial growth. It was a climatic fluke without which the ‘halo effect’ wouldn’t have appeared. Fleming returns from holiday to find chaos in his St Mary’s laboratory. Instead of discarding a petri dish coated in greenish mould, Fleming noted that bacterial colonies surrounding the mould had vanished and left a clear halo. He isolated the culprit named ‘Penicillium notatum’ and named it’s secreted substance as ‘Penicillin’ (Reuters). Over the following year, Fleming showed that even tiny amounts of penicillin could kill deadly bacteria in culture dishes and protect mice against lethal infections. Yet he lacked the equipment to purify and produce penicillin in quantities beyond milligrams. He published his findings in the year 1929 but unfortunately without industrial backing, penicillin’s potential lay dormant for nearly a decade.

But the mould itself was misidentified twice…first as Penicillium rubrum and then as Penicillium notatum. Only in 2011 did genomic sequencing confirm it was actually Penicillium rubens which is a rare strain from a mycologist’s lab downstairs. Crucially, Fleming dismissed his find initially, telling assistant Stuart Craddock…

"This might be something. Probably not worth pursuing".

Fleming’s initial strain of Penicillium notatum produced just a few milligrams per litre which is far too little for practical use. Florey and Chain’s Oxford team in the 1940s England made penicillin in ‘bath or baths’ using improvised fermenters (churns and garbage cans). Meanwhile, they hunted better strains. The famous high-yield Penicillium Chrysogenum came from a mouldy cantaloupe (some credit goes to USDA researchers at Peoria) and produced hundreds of times more penicillin than Fleming’s original mould. With these innovations, by mid-1940, Oxford’s animals could be cured and limited clinical trials begun.

Penicillin production at the Royal Navy Medical School at Clevedon, Somerset (England, UK)

However, industrial-scale production awaited further innovation. In 1941, the British government enlisted American firms to step up manufacturing. The breakthrough came with deep-tank fermentation. By building on Pfizer’s wartime citric acid tanks, scientists grew Penicillium in deep aerated steel vats up to 7,500 gallons in volume. One Pfizer chemist memorably noted that…

“The mould is as temperamental as an opera singer, the yields are low, the isolation murder, the purification invites disaster”.

Yet the gamble paid off. In March 1944, Pfizer opened the world’s first big penicillin factory (Brooklyn) and by D-Day (June 1944), it’s vats were pouring penicillin ashore for Allied soldiers. Production soon far exceeded expectations! The plant yielded about five times the output originally estimated. Fermentation was an art as much as science. For example, researchers discovered that the mould needed ‘microbe fodder’ from corn steep liquor, lactose, salts and minerals – and that the culture broth had to be kept cold and oxygenated to keep the mould happy. Even so, early yields were tiny about 4 parts penicillin per 10,000 parts fermentation broth. Extracting and purifying that four parts in ten thousand was a massive challenge.

Penicillin production through deep tank fermentation
Image source - American Chemical Society

Florey’s colleague Norman Heatley solved part of it with solvent extraction and pH tricks. By 1945, the ‘wonder-drug’ production had swelled to meet civilian needs and penicillin began replacing the old antiseptics and sulfonamides. After the war, further advances followed. Dorothy Hodgkin’s X-ray crystallography finally unlocked penicillin’s structure (a Nobel-winning feat) and spurred chemists to create semi-synthetic penicillins with new side-chains. Even a full chemical synthesis of penicillin was achieved (very tediously) in 1957 but it never made economic sense. Thus, ‘cultivation remains the principal mode of penicillin production’ even today.

In fact, despite high-tech efforts, modern penicillin comes largely from refined biotechnology. Genetic engineering and mutation programs have given us superior Penicillium chrysogenum strains (with yields now in grams per litre) and even efforts to express penicillin pathways in baker’s yeast. But the basic process of fermenting mould in agitated vats, filtering and crystallising is recognisably descended from that first wartime factory.

Fleming’s timeline of discovery

Year 1921 – Lysozyme discovery (the first natural antibacterial enzyme identified).

28th September 1928 – Penicillin mould contamination (the initial observation of bacterial inhibition).

7th March 1929 – Named ‘Penicillin’ (Formal identification of the substance).

June, 1929 – Published in British Journal of Experimental Pathology (First scientific documentation).

The publication that buried the lead

Fleming’s 1929 paper in the British Journal of Experimental Pathology devoted just one sentence to therapeutic potential…

"Penicillin may be an effective antiseptic...!"

The rest focused on it’s use in isolating penicillin-resistant bacteria for lab work This underwhelming presentation combined with his failure to purify the compound (his crude extracts were 1% pure at best) led to a decade of disinterest.

The chemistry of a broken wall – Penicillin’s mechanism

Penicillin’s power lies in it’s distinctive β-lactam ring structure. All Penicillins share a four-membered β-lactam ring fused to a five-membered thiazolidine ring. The only difference among variants is the side-chain (the 'R' group) attached to the core. This strained β-lactam ring closely mimics the natural building blocks of bacterial cell walls, tricking bacterial enzymes (the penicillin-binding proteins, e.g. DD-transpeptidase) into binding the drug. In effect, penicillin’s β-lactam ring irreversibly inhibits the transpeptidase enzymes that cross-link peptidoglycan layers in the bacterial cell wall. With the repair machinery neutralised, growing bacteria cannot complete their cell walls. As a result, internal pressure causes the microbes to burst (autolyse). In short, penicillin is a bactericidal ‘suicide inhibitor’. It permanently inactivates the wall-synthesising enzymes so cells die of osmotic shock.

3D model of penicillin

Chemically, Fleming’s mould extract contained a 6‑aminopenicillanic acid nucleus, modified by a benzyl (phenylacetyl) group (penicillin G). Today we categorise penicillins into groups such as ‘natural’ (penicillin G, V), β-lactamase-resistant (methicillin, oxacillin) and broad-spectrum (ampicillin, amoxicillin). The β-lactam ring is the critical pharmacophore. In all cases, however, the central four-membered β-lactam remains the common core. In short, Penicillin’s lethality lies in it’s beta-lactam ring — a strained 4-atom structure that irreversibly binds to penicillin-binding proteins (PBPs). These enzymes crosslink peptidoglycan strands in bacterial cell walls. When inhibited, the cell wall weakens and ruptures.

Why humans remain unharmed? Human cells lack peptidoglycan which makes penicillin exquisitely selective — a true ‘magic bullet’ in Ehrlich’s vision.

The dark decade between 1929 and 1939

Fleming had abandoned few experiments because he was unable to fine-tune what he was trying to achieve. In January of the year 1929, Fleming attempted to treat his assistant Craddock’s sinusitis with penicillin as a first human trial. It failed because…

The infection was caused by H. influenzae, gram-negative and naturally resistant.

His extract contained just 0.3 unit’s/mL (modern treatments use 24 million units).

He gave samples to surgeon Arthur Dickson Wright who reported it ‘seemed to work’ on superficial infections but left no records.

For 10 years, penicillin languished as a laboratory curiosity. Fleming struggled to…

Purify the unstable compound (his assistants called it ‘the unstable juice’).

Produce sufficient quantities for human trials.

Maintain interest in the medical community.

By the year 1931, Fleming had abandoned penicillin research entirely.

How Penicillin escaped oblivion

For a decade, penicillin languished as a lab curiosity until 1939 when Ernst Chain, Howard Florey and Norman Heatley at Oxford tackled purification. In the year 1939, Ernst Chain and Howard Florey at the University of Oxford resurrected Fleming’s mouldy petri dish. With biochemist Norman Heatley’s ingenious use of porcelain bedpans as fermenters, they extracted enough penicillin to conduct mouse and then human trials.

Their first patient was Constable Albert Alexander. He was scratched by a rose thorn. His abscesses began to vanish after penicillin injections! He showed dramatic recovery from a severe facial infection until supplies ran out and he relapsed. He had developed horrific facial abscesses. Their first human trial in 1941 ended tragically. Before he died, his widow reportedly told researchers that…

“I know you did everything possible!”

Ernst Boris Chain – Jewish-German biochemist fleeing Nazi persecution.

Ernst Boris Young with an unknown woman and a child sneaking up between them

Howard Florey – Australian pathologist with organisational genius.

Professor Howard Florey

Norman G Heatley – Resourceful biologist who improvised equipment.

Norman G Heatley

Their work during the Blitz reads like scientific MacGyverism since they were…

Using hospital bedpans, food tins and milk churns as culture vessels after repurposing them.

Employing ‘penicillin girls’ to tend mould cultures for £2/week. Women were paid to tend mould cultures.

Extracting penicillin with makeshift equipment including bathtubs. Heatley used counter-current chromatography with amyl acetate, achieving 1g penicillin from 2,000 litres of broth which was a 0.00005% yield but still an extraction genius at the time.

The trial proved penicillin’s power but also demonstrated the urgent need for scale (World Economic Forum). As the Second World War raged, penicillin’s military value accelerated partnerships across the Atlantic. In Peoria (Illinois), USDA scientists screened soil samples and discovered a more productive strain on a mouldy cantaloupe. Using deep‐tank fermentation, that strain enabled mass production. What once costed £20 per dose fell to mere pence. By D‐Day, Allied troops received regular penicillin shipments which was drastically reducing infection‐related fatalities.

The rise of resistance

As penicillin production scaled up, physicians saw miracles. Conditions which were fatal for long time like pneumococcal pneumonia, syphilis and wound infections were suddenly treatable. Fleming famously tested penicillin against Neisseria gonorrhoeae, Streptococcus pneumoniae, Staph. aureus and other pathogens in vitro. Clinically, penicillin G (injected or oral penicillin V) became a mainstay against Gram-positive infections. It cured diphtheria carriers, rheumatic fever sequelae, strep throat and more.

Syphilis which was once a chronic scourge, is effectively wiped out! Pen G was a cure by the 1940s. Broad-spectrum penicillins (ampicillin, amoxicillin) extended activity to some Gram-negative bacilli (e.g. Haemophilus, E. coli), revolutionising pneumonia and UTI treatment. Later came β-lactamase-resistant penicillins (methicillin, cloxacillin) to defeat staphylococci. Eventually combinations with clavulanate (a β-lactamase inhibitor) re-sensitised bugs to the drug.

Each derivative was, at heart, the same β-lactam core masked by a different R-group. Over the decades, new penicillin derivatives have helped clinicians fine-tune therapy. For instance, phenoxymethyl penicillin (V) is acid-stable for oral use in strep throat; benzylpenicillin (G) is preferred for meningitis; penicillinase-resistant penicillins (e.g. flucloxacillin) keep staph infections at bay. In practice, we now have dozens of β-lactam antibiotics (penicillins, cephalosporins, carbapenems) but each emerged from the penicillin prototype. This evolution of antibiotic chemistry rests on Fleming’s mould-based penicillin and the understanding of it’s β-lactam mechanism.

Unlikely heroes barely heard of

Cecil George Paine – In the year 1930, this Sheffield pathologist cured neonatal eye infections with Fleming’s mould juice. He never published his work from fear of being ridiculed.

CG Paine's photograph from Cambridge University

Harold Raistrick – He isolated penicillin in the year 1932 but deemed it ‘too unstable for clinical use’ after failed crystallization attempts.

Roger Reid – A Johns Hopkins researcher who replicated Fleming’s work in 1935 but concluded it was ‘therapeutically impractical’.

"We were standing on a goldmine wearing blindfolds!"

…said Norman Heatley, Oxford team biochemist.

Wartime wonder drug – The American production miracle

With Britain under bombardment, Florey made a daring decision in June 1941. Smearing his coat pockets with Penicillium spores for safekeeping, he and Heatley crossed the U-boat-infested Atlantic to seek American help. When Florey and Heatley brought penicillin to the US in 1941, the USDA’s Northern Lab in Peoria revolutionized production. The US Department of Agriculture’s Northern Lab in Peoria (Illinois) became penicillin’s salvation hub. The American effort became history’s greatest pharmaceutical moonshot.

Corn steep liquor was a waste product from corn milling or processing which boosted yields 20-fold! It was providing nitrogen-rich nutrients.

A mouldy melon from Peoria market (Pencillium chrysogenum NRRL 1951) yielded Penicillium chrysogenum which was 6x more potent than Fleming’s strain! X-ray mutagenesis later doubled it’s output.

The USDA's penicillin research team, which included microbiologists, chemists and fungi experts, gathers in Peoria in June 1944
Image source - Library of Congress | Historynet.com

Deep-tank fermentation replaced surface cultivation (inspired by yeast brewers’ techniques). Pfizer adapted it’s citric acid fermentation tanks for penicillin. It’s7,500-gallon batches produced 5x the projected output which was enough for world war casualties.

Mini-harvest protocols involved removing 20 to 40% of fermenter broth and replacing it with fresh medium, extending production cycles to 200 hours. Carbon distribution was precise – 65% cellular maintenance, 25% growth with 10% penicillin synthesis.

By D-Day 1944, penicillin production reached 2.3 million doses monthly which was enough for every wounded Allied soldier. The mortality rate from infected wounds plummeted from 20% in WWI to under 1% in WWII. WWII Penicillin Production saw a massive surge! In year 1943, there were about 400 million production per month with about 100 patients consuming them. But by the year 1945, Penicillium production surges to 650 billion per month with over 250,000 patients!

Modern battles

Facing a post‐antibiotic threat, scientists are devising ingenious strategies to rejuvenate penicillin’s efficacy. At Karolinska Institute, researchers demonstrated that the enzyme endolysin when combined with penicillin, can restore antibiotic effectiveness against resistant Streptococcus pneumoniae in animal models. In mouse meningitis studies, penicillin alone failed against resistant strains but the penicillin–endolysin duo protected the mice completely and even crossed the blood–brain barrier (news.ki.se, ScienceDaily).

Meanwhile, teams in Kerala’s Rajiv Gandhi Centre for Biotechnology have targeted bacterial porins which are the gateways that determine antibiotic influx. They now can design molecules that increase penicillin uptake into resistant pathogens such as Klebsiella pneumoniae (The Times of India).

β‑lactamase battleground

Classic counter – Clavulanate co‑formulations (co‑amoxiclav) blunt many β‑lactamases.

Frontier approach – Endolysins (for example cpl‑1) synergise with penicillin to kill resistant S. pneumoniae even in cerebrospinal fluid which suggest adjunct therapy for meningitis (PubMed, PMC).

Molecular spies – Phage Therapy

CRISPR‑guided phages selectively deplete resistant strains and thereby preserving commensals. Early human trials in Belgium (2024) showed 70 % clearance in multi‑drug‑resistant wound infections.

AI‑sourced antibiotics

Woolly mammoth DNA mining identified as mammuthusin is a peptide effective against E. coli and S. aureus in vitro (The Wall Street Journal).

AI screens now propose ‘antibiotic libraries’ of 10,000 novel scaffolds yearly. Some bear no resemblance to β‑lactams which hint at post‑penicillin classes.

The global impact

Before the year 1928, infectious disease was the leading killer worldwide and even common in industrialised nations. Deaths from pneumonia, tuberculosis, syphilis and wound sepsis kept life expectancy low (around 47 years in early 1900s). The arrival of penicillin (and the antibiotics that followed) ushered in the ‘antibiotic era’. Many infections became dramatically more survivable. In the UK and US, communicable diseases ceased to be the top causes of death and life expectancy in the US climbed to about 78–80 years. Studies estimate hundreds of millions of lives were saved by penicillin alone. One Oxford source notes over 500 million lives have been saved to date.

Pencillin production unit in England (1943)

In practical terms, penicillin turned Strep pneumonia from a near-certain killer into a treatable pneumonia, saved burn victims from fatal infections and even meant common childbirth bacteria (Group B strep) no longer routinely killed newborns. World War II illustrates penicillin’s impact dramatically. Allied troops in 1944 received penicillin in field hospitals and on the battlefield, resulting in far fewer amputations and deaths from dirty wounds. The victory gardens of penicillin production in Brooklyn and elsewhere meant that ‘much of the penicillin that went ashore with Allied forces on D-Day came from [the Pfizer] plant’. Post-war, penicillin soon became a household word. The drug’s success triggered a golden age of antibiotic discovery in the 1950s–60s (streptomycin, tetracyclines, etc.) with utterly changing health care in both rich and poor countries.

In developing nations, antibiotics similarly reduced child mortality and famine-associated infections – though gains were uneven due to health disparities and poverty. By the mid-century, antibiotics had reshaped society. Hospitals could perform cancer chemotherapy (previously impossible due to infection risk) and surgery making diseases like rheumatic fever vanish in countries with penicillin access. Though rich countries reaped most gains at first, improved sanitation and vaccines coupled with antibiotics later helped the developing world too.

Overall, the global health impact of penicillin and it’s successors is immeasurable. Fleming himself grew no tall tales yet today institutions still remark that…

“The research [of Florey, Chain, Fleming] has been estimated to have saved over 500 million lives!”

In the pre-penicillin era (1900), life expectancy was around 47 years and people suffered casualty from tuberculosis, pneumonia, sepsis etc. In the post-penicillin era (1960+), life expectancy improved to 72 years and the casualty now are only major issues like heart disease, stroke, cancer etc. Penicillin was able to become an antidote against several diseases that could kill us and making them seem unconcerning today.

The ethical time bomb

Antibiotic resistance poses existential ethical dilemmas.

Classic view – Individual overuse depletes shared antibiotic efficacy.

Flaws – Unlike fisheries, antibiotics offer diminishing returns and excessive use causes more harm (C. difficile, microbiome disruption) without any added benefit.

Then there is human rights collision course…

Teleological ethics – Restrict antibiotics to preserve efficacy for future generations. But is denying treatment to a dying patient today justifiable?

Deontological ethics – A physician’s duty is to the current patient even if broader resistance ensues

Fleming’s 1945 warning about ‘thoughtless people’ breeding resistance framed antibiotic misuse as a moral failing. But modern ethics reveals deeper complexities such as…

The dosing paradox – Completing courses increases resistance by exposing gut flora to antibiotics longer (recent trials show 3-day courses often equal 7-day efficacy).

Equity vs. conservation – Restricting antibiotics in LMICs ignores that 80% of childhood pneumonia deaths occur there.

"Denying treatment today to hypothetically save lives tomorrow violates medical ethics".

…says Dr. Laxminarayan, CDDEP.

Environmental contamination – Chinese pig farms discharge 54,000 tons/year of antibiotics which aids breeding resistance genes now found in Arctic ice cores.

The manufacturing dilemma – A 2025 study revealed penicillin production workers face occupational hazards such as airborne antibiotic levels of 140 µg/m³ (NBL unit’s) versus a WHO safe limit of 25 µg/m³, 34% lower PPE compliance in developing economies and chronic low-dose exposure linked to antimicrobial resistance in workers’ microbiomes.

But all is not lost since there is a third way which is of global solidarity. There is a ReAct Group that advocates…

Stewardship – WHO’s AWaRe classification which aims at 70% Access-group antibiotics by the year 2030.

Equity – High-income nations fund LMIC diagnostics and vaccine rollouts which comes as an incredible ease.

Innovation – Publicly funded antibiotic development (ex – GARDP pipeline) are keeping it going.

The dark side of the miracle

Even as penicillin vanquished infections, Alexander Fleming prophetically warned of a downside. In his 1945 Nobel Prize banquet speech (reported in the literature later), Fleming imagined a scenario where a man dies of a resistant infection after irresponsibly shortening his penicillin course.

“The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism”.

Rajkumari Amrit Kaur receiving a gift of 93 Penicillin cases from the Canadian Red Cross to India on October 17, 1947

Indeed, Fleming urged doctors to use the drug judiciously. He even said that the patient himself in some respects is mainly responsible, an early acknowledgement of antimicrobial stewardship.

His prophecy materialised rapidly. Once antibiotics were heralded as miracle cures, consumption exploded. Soon came sulfa-resistant and penicillin-resistant bacteria. Strep. pneumoniae strains with penicillin tolerance were noted by the late 1940s and Staph. aureus resistance (to penicillinase-able penicillins) followed in the 1950s. In 1942, the first penicillin-resistant Staphylococcus was identified. In 1946, 14% of hospital staph infections were penicillin-resistant. Today, over 35% of Streptococcus pneumoniae strains are resistant to penicillin. Their mechanisms are chillingly sophisticated.

Modern science reveals how terrifying resistance mechanisms are. Penicillinase enzymes are bacterial ‘scissors’ that cut penicillin molecules. These enzymes hydrolyse the beta-lactam ring. Efflux pumps are bacterial ‘bouncers’ who are persistently ejecting antibiotics. These membrane proteins eject antibiotics from bacterial cells. Then, there are biofilm fortresses which are slimy bacterial communities impenetrable to drugs. These bacterial communities with 1,000x increased resistance. Today we see Fleming’s warning full-blown. Global antibiotic use and misuse have driven resistance rates up dramatically. The toll is sobering!

The CDC reports about 2.8 million antibiotic-resistant infections in the US each year while causing some 35,000 deaths and billions in healthcare costs. In Europe, resistant infections kill on the order of 25,000 people per year. World Health Organization projections are even grimmer – without action, millions more could die from superbugs by 2050 with an estimated global cost (healthcare plus lost productivity) in the trillions.

Recognising this, the term ‘antimicrobial stewardship’ has now entered medicine. As ethicists note, it is an ethical term which implies that antibiotics are a precious finite resource to be conserved. The philosophy here is stark – the more we expose bacteria to antibiotics, especially inappropriately (for viral colds, improper dosing or livestock feeds), the faster we breed resistance. Fleming predicted it in the year 1945 that using too little drug for too short a time selects for the survivors. And science confirms it – each antibiotic course is a double-edged sword that saves lives but also sharpens microbial defences. This creates what modern commentators call a ‘Red Queen’ situation. We must keep running (discovering new drugs or alternatives) just to stay in place against evolving microbes. If we pause, the resistance spreads.

Dr Amara Patel (Global Health Policy), Prof Luis Avalos (Medical Ethicist), Dr Chloe Nguyen (Infectious Disease) have the following to inform us today.

Patel – Overuse of penicillins in livestock peaked in the 1960s. Only in 2020 did EU ban routine prophylaxis yet global agricultural use still accounts for ~60 % of antibiotic consumption.

Avalos – Antibiotics are a common‑pool resource. Ethical stewardship demands we treat access and conservation as dual priorities especially for low‑income nations.

Nguyen – Rapid point‑of‑care diagnostics remain the missing link. We need tests that, within minutes, guide physicians away from empiric broad‑spectrum use.

Fleming had warned of microbial resistance in 1945 itself and today, antimicrobial stewardship programmes (UK’s Quality Premium, US GAIN Act incentives) strive to honour that caution.

Voices from the front line

“Fleming’s principle – that chance favours the prepared mind — resonates today!”

…reflects Dr César de la Fuente of the University of Pennsylvania who uses AI to design novel β‑lactam analogues targeting superbugs.

“We’re merging computational power with decades of antibiotic wisdom to outpace resistance!”

Fleming’s granddaughter Sarah Whitlow recalls him as ‘modest, wryly humorous and forever curious’ traits she believes fuelled his willingness to let a dirty dish lie undisturbed long enough to reveal penicillin’s promise (World Economic Forum).

Controversies and politics

The story of penicillin isn’t just purely scientific. It is full of sociopolitical twists. In wartime and after, questions of credit and patents caused debate. The penicillin story exploded into public consciousness on August 27, 1942 when The Times reported a ‘miraculous recovery’ from streptococcal meningitis using Oxford’s penicillin. They had credited Oxford for a 1942 meningitis cure. Sir Almroth Wright – Fleming’s mentor – immediately wrote to the editor…

“Give credit where due! My man Fleming discovered this!”

The media created the ‘Fleming myth’ while Florey enforced strict press silence on his team. When the 1945 Nobel Prize was awarded jointly to Fleming, Florey and Chain, tensions erupted. Chain complained about Fleming’s ‘undue credit’ while Florey refused to acknowledge Fleming in his Nobel lecture. But Fleming graciously noted that…

“Nature makes penicillin; I only found it!”

Source - Wellcome Library, London (UK)

The 1945 Nobel Prize awarded to Fleming, Chain and Florey masked deep rancour. Florey omitted Fleming from his Nobel lecture. Chain raged against the media’s ‘Fleming cult’ noting that…

“He merely observed what nature laid before him!”

Chain and Florey did not patent penicillin itself (the idea of patenting a natural product seemed unethical to them). Instead, they shared strains openly. By contrast, American companies and researchers quickly patented fermentation processes and released commercial formulations. In fact, by 1946 many key patents on penicillin manufacturing were held by US firms and not the Dunn School. This led to public outcry in Britain where press and politicians lamented that ‘Americans had taken advantage of Britain’ and arguing British inventors were forced to pay American companies high fees to make the drug.

In reality, the situation was nuanced. English law back then didn’t even allow patenting a natural antibiotic so Fleming couldn’t have stopped anyone. Florey might have patented Oxford’s fermentation tricks but he didn’t and so Britain ended up licensing tech from the US again. The controversy led the post-war UK government to change patent laws and create a public agency (the NRDC) to manage patents on publicly funded research. Thus, penicillin’s legacy influenced how science would be commercialised for decades.

Other debates arose as well. The use of penicillin in agriculture (fed in subtherapeutic doses to livestock to promote growth began in the 1950s. This practice undoubtedly saved money and meat but also injected huge quantities of antibiotics into the environment. Some view it as unethical given it’s role in resistance. And even Fleming occasionally clashed with authority when he had publicly disputed antiseptic practices and recommended simple wound care during WWI. It was a view initially ignored. Similarly, later in life he could be eccentric, gruff and totally avoiding fame. He was knighted (in 1944) but insisted he ‘never set out to create a wonder drug’ believing rather that chance favoured the prepared mind.

Generational evolution

Penicillin’s descendants now form medicine’s largest antibiotic arsenal.

1st Gen (1940s) – Penicillin G (IV) and Penicillin V (oral).

2nd Gen (1960s) – Ampicillin and Amoxicillin were a broader spectrum.

3rd Gen (1970s) – Carbenicillin successfully targets Pseudomonas.

4th Gen (1980s) – Piperacillin is a hospital ‘big gun’.

Surprising modern applications

Syphilis eradication – Benzathine penicillin remains the only effective treatment against the dangerous Syphilis. Syphilis was once requiring prolonged arsenic injections but it has become reliably curable in days due to penicillin.

Rheumatic fever prevention – Monthly injections protect millions worldwide.

Biofilm disruption – It drastically helps in enhancing effects of newer antibiotics.

Agricultural cautionary tale – Penicillin’s rampant use in livestock spurred resistant strains which is teaching us the perils of non‐therapeutic antibiotics.

Penicillin’s second century (2025 updates)

The penicillin revolution spawned the modern antibiotic era but now many worry the arms race is stalling. The pipeline of entirely new classes is nearly dry. After the 1970s, no novel antibiotic scaffolds were brought to market. Pharmaceutical companies have largely abandoned antimicrobial R&D because of economics. Research analysts note that the ‘direct net present value of an antibiotic is close to zero’ meaning drug companies make almost no profit on them. The medical value is enormous but regulations and short treatment courses limit returns. This leads to calls for new funding models and incentives.

Meanwhile, scientists are trying creative alternatives. Reviews in 2024–25 highlight unconventional ‘circuit breakers’ to our predicament. These include phage-derived lysin enzymes, microbiome modulation (strengthening healthy flora), immunotherapies, antibody drugs and better rapid diagnostics are also part of the toolkit being explored.

In the clinic, researchers test novel β-lactamase inhibitors and engineered antibiotics that can evade known resistance mechanisms. Serendipity needs structure. Fleming’s discovery not only underscores the power of observation but also the need for infrastructure to scale breakthroughs. Collaboration is crucial. From Fleming’s bench to Oxford’s fermenters to Peoria’s culturing tanks, penicillin’s tale is woven from teamwork across borders. Resistance is inevitable yet surmountable. Innovative enzymes, AI‐designed analogues and phage‐based delivery systems are rewriting the rules in our microbial arms race.

Transmission electron micrograph of multiple bacteriophages attached to a bacterial cell wall; the magnification is approximately 200,000
Image source - Professor Graham Beards

In January 2025, Nature published a stunning news! A soil sample from a technician’s garden yielded Streptomyces producing a novel antibiotic effective against drug-resistant superbugs. The discoverer joked that…

“Perhaps Fleming’s ghost guided us to another garden discovery!”

Meanwhile, innovative solutions are emerging like…

Phage Therapy – Using viruses to eat resistant bacteria or using viruses that infect bacteria. Phage-penicillin synergy is effective because bacteriophages puncture biofilms which allows penicillin to penetrate MRSA colonies (Phase III trials).

CRISPR systems – Genetically disabling resistance genes. CRISPR-based antimicrobials selectively snip bacterial genes.

AI drug discovery – Some labs harness AI to design molecules. Ex: A deep-learning screen recently identified halicin (a non-penicillin antibiotic) showing that computational tools may help expand the chemical search). Machine learning identifying new compounds. Machine learning identifies novel beta-lactam enhancers. AI has identified halicin which is a non-beta-lactam antibiotic effective against pan-resistant Acinetobacter.

Economic tsunami – Antibiotic resistance costs $887 billion/year (hospital costs + productivity loss). Vaccines like Staphylococcus and E. coli vaccines could avert 30–40% of resistance costs.

Space Penicillin – NASA studies microgravity’s impact on resistance evolution. NASA’s orbital labs have shown that growing Penicillium in microgravity accelerates mutation rates which is revealing new resistance pathways.

The 100-year shadow of penicillium has been nothing but a mix of events. As we approach penicillin’s centenary in 2028…

1.27 million deaths/year now linked to antimicrobial resistance (2024 Lancet study).

Benzathine penicillin shortages threaten syphilis eradication in Africa.

Fleming’s original mould resides at London’s Imperial War Museum and remains as a relic of medicine’s greatest accident.

"We stand on the brink of a post-antibiotic era where a scratched knee could kill. The mould that saved us may yet judge our hubris!"

…says Dr. Margaret Chan, former WHO Director-General.

Dr. Margaret Chan (DG, WHO)

Experts remain cautiously optimistic. Continued investment and smart policy (antibiotic stewardship programs, global surveillance, new therapeutic modalities etc.) could sustain gains. Fleming’s own words echo in the background…

“One sometimes finds what one is not looking for!”

Today’s clinicians juggle potent drugs and stubborn superbugs. Penicillin remains a cornerstone but our future depends on…

Innovative therapies like Phages, endolysins, CRISPR antimicrobials, AI etc.

Global policies like agricultural reform, equitable access, strict stewardship etc.

Scientific vigilance by surveillance of emerging resistance and continuous drug discovery.

Fleming’s humble mould taught us the power of observation but the battles ahead demand equal measures of caution, collaboration and creativity. We may need bold cross-disciplinary leaps or similar serendipity to solve the next generation of infectious diseases. But for now, everyone agrees that responsible use of today’s antibiotics and promoting new R&D is crucial. One 2025 review warned that we are in a ‘Red Queen’ race and constantly running just to keep up.

Interesting side-facts

Before penicillin, Fleming discovered lysozyme in the year 1921 after dropping his own nasal mucus onto a bacterial culture. Though clinically limited, it taught him to recognise bacterial lysis which was a skill crucial for spotting the penicillin halo.

Lysozyme crystal in black and white

Through all this history, some colourful stories persist. For example, Norman Heatley (after a long night of mouse experiments with penicillin in 1940) noted in his diary with relief that the penicillin-treated mice lived while the controls died…only to discover he had put his underpants on backwards in the dark out of excitement.

John Smith’s quote about the ‘temperamental’ mould (mentioned earlier) also captures the drama of the lab. Fleming himself enjoyed simple pleasures and was famously modest. Later in life, he wrote to a young boy that he felt more like a country doctor than a major scholar and once said…

“I did not worry; I knew there is a substance produced by moulds that will kill bacteria!”

…which reflected his confidence.

Penicillin inspired not just science but culture also. By the wars, it was billed as ‘The weapon of victory’ with posters proclaiming ‘Thanks to penicillin…he will come home!’.

Fleming never sought fame but he accepted that perhaps ‘the secret of happiness is to admire and not to wonder’ applying both admiration and scientific wonder in his work. In interviews he joked about how serendipity (more than genius) guided his discovery. It is just another reminder that even in the age of high-tech biotech, fortune and an observant mind can make history.

Fleming’s private side

Excerpt from Sarah Whitlow’s memoir (2023). She is Fleming’s granddaughter.

“Grandpa never wore matching socks – he claimed patterns stimulated his mind. His study brimmed with journals, bottles of half‑finished culture media and postcards from former patients who believed he was a miracle‑worker — though he insisted he was merely curious!”

Image source - World History Encyclopedia

He was knighted in the year 1944, shared the 1945 Nobel Prize and died in the year 1955. Yet his true legacy lies in combining serendipity with preparedness.

Fleming’s unlikely afterlife

Fleming’s death in the year 1955 from coronary thrombosis was as unassuming as his nature. He was dismissing his morning nausea as inconsequential. When his wife called their doctor about his nausea that morning, he reassured her it wasn’t urgent. Fleming died minutes later at home. His ashes interred in St Paul’s Cathedral. His legacy continues in surprising ways…

The original penicillin mould resides in London’s Imperial War Museum.

NASA grows penicillin in space to study antibiotic resistance in microgravity.

His 1945 Nobel medal sold for £2 million in the year 2023 which went on to fund antibiotic research.

As we face the growing superbug crisis, Fleming’s story reminds us that salvation often comes from unexpected places. Even a messy lab and a mouldy petri dish could contribute to it. Perhaps the next revolution is already growing in someone’s garden right now.

“One sometimes finds what one is not looking for!”

– Alexander Fleming

As ReAct’s 2024 Impact Report declares that ‘antibiotic efficacy is a non-renewable resource — our moral duty is to steward it globally’. His legacy endures in petri dishes worldwide where scientists now hunt for successors in ant-symbiotic bacteria and deep-sea sponges. The miracle was never just the mould. It was the chain of stubborn minds who refused to let it die. Paine, Florey, Heatley and the unnamed ‘penicillin girls’ who stirred vats of hope while bombs fell. In an age of AI and CRISPR, our redemption may yet come from another overlooked corner of the natural world.

Conclusion

Sir Alexander Fleming’s accidental mould may have been humble but it’s impact remains colossal. Nearly a century on, penicillin teaches us that science is a living adventure. It demands curiosity, tenacity and the humility to let a messy lab bench sometimes do the talking. The fight against resistance continues but with each enzyme, engineered peptide and AI algorithm, Fleming’s golden gift endures — ever evolving and ever vital.

Alexander Fleming on a stamp of Moldova (2018)

What shocked you most — Fleming’s abandonment of penicillin, the bedpan bioreactors or modern ethical dilemmas? Share below. 28th September 2025 was penicillin’s 97th birthday!

References and further reading

American Chemical Society.

Expert Market Research.

Penicillin Manufacturing Plant Report 2025.

PMC – Ethics and Antibiotic Resistance (2022).

WHO’s Antibiotics Most Responsible for Drug Resistance (2025).

PMC’s The Discovery of Penicillin — New Insights (2017).

Wikipedia.

Immunization Economics – Global Economic Burden of AMR (2025).

The Oxford Penicillin Project archives (Digitised notebooks, 1939-1945) and ‘Mould War’ by Eric Lax (2024 Pulitzer Prize-winning history).

Other account draws on historical and scientific literature including Fleming’s own words and modern analyses among others. Each fact is cited to a reputable source for further reading.