At the beginning of the 20th century, Paul Ehrlich pioneered the search for a chemical that would kill a microorganism and leave the host unaltered—the “magic bullet.” Ehrlich also coined the term chemotherapy: “There must be planned chemical synthesis: proceeding from a chemical substance with recognizable activity, making derivatives from it, and then trying each to discover the degree of its activity and effectiveness. This we call chemotherapy” (2). After extensive testing, he found a drug with activity against the bacterium Treponema pallidum, which causes syphilis. The introduction of this drug, arsphenamine (Salvarsan), and its chemical derivative neoarsphenamine (Neosalvarsan) in 1910 ushered in a complete transformation of syphilis therapy and the concept of chemotherapy. Unfortunately, despite exhaustive searches, the promise of more magic bullets for microbial therapy remained elusive. For 20 years, Salvarsan and Neosalvarsan were the only chemotherapy for bacterial infections.

A chance event in a London laboratory in 1928 changed the course of medicine. Alexander Fleming, a bacteriologist at St. Mary’s Hospital, had returned from a vacation when, while talking to a colleague, he noticed a zone around an invading fungus on an agar plate in which the bacteria did not grow. After isolating the mold and identifying it as belonging to the Penicillium genus, Fleming obtained an extract from the mold, naming its active agent penicillin. He determined that penicillin had an antibacterial effect on staphylococci and other gram-positive pathogens.

Fleming published his findings in 1929 (3). However, his efforts to purify the unstable compound from the extract proved beyond his capabilities. For a decade, no progress was made in isolating penicillin as a therapeutic compound. During that time, Fleming sent his Penicillium mold to anyone who requested it in hopes that they might isolate penicillin for clinical use. But by the early 1930s, interest had waned in bringing to life Paul Ehrlich’s vision of finding the magic bullet.

This dismal outlook on chemotherapy began to change when Gerhard Domagk, a German pathologist and bacteriologist, found bacteriologic activity in a chemical derivative from oil dyes called sulfamidochrysoïdine (also known as Prontosil). This compound had bacteriologic activity in animals, but strangely, none in vitro. Prontosil had limited but definite success when used to treat patients with bacterial infections, including Domagk’s own child. A German company patented the drug, and ultimately, Domagk won a Nobel Prize in 1939. The paradox of Prontosil’s in vivo success but lack of success in vitro was explained in 1935, when French scientists determined that only part of Prontosil was active: sulfanilamide. In animals, Prontosil was metabolized into sulfanilamide. Within 2 years, sulfanilamide and several derivative sulfa drugs were on the market. The success of sulfanilamide changed the cynicism about chemotherapy of bacteria (1).

The success of sulfa drugs sparked interest in finding other agents. At Oxford University, Ernst Chain found Fleming’s 1929 article on penicillin and proposed to his supervisor, Howard Florey, that he try to isolate the compound. Florey’s predecessor, George Dreyer, had written Fleming earlier in the 1930s for a sample of his strain of Penicillium to test it for bacteriophages as a possible reason for antibacterial activity (it had none). However, the strain had been saved at Oxford. In 1939, Howard Florey assembled a team, including a fungal expert, Norman Heatley, who worked on growing Penicillium spp. in large amounts, and Chain, who successfully purified penicillin from an extract from the mold. Florey oversaw the animal experiments. On May 25, 1939, the group injected 8 mice with a virulent strain of Streptococcus and then injected 4 of them with penicillin; the other 4 mice were kept as untreated controls. Early the next morning, all control mice were dead; all treated mice were still alive. Chain called the results “a miracle.” The researchers published their findings in The Lancet in August 1940, describing the production, purification, and experimental use of penicillin that had sufficient potency to protect animals infected with Streptococcus pyogenes, Staphylococcus aureus, and Clostridium septique (4).

After the Oxford team had purified enough penicillin, they began to test its clinical effectiveness. In February 1941, the first person to receive penicillin was an Oxford policeman who was exhibiting a serious infection with abscesses throughout his body. The administration of penicillin resulted in a startling improvement in his condition after 24 hours. The meager supply ran out before the policeman could be fully treated, however, and he died a few weeks later. Other patients received the drug with great success. The Oxford team then published their clinical findings (5). At the time, however, pharmaceutical companies in Great Britain were unable to mass produce penicillin because of World War II commitments. Florey then turned to the United States for assistance.

In June 1941, Florey and Heatley traveled to the United States. Concerned about the security of taking a culture of the precious Penicillium mold in a vial that could be stolen, Heatley suggested that they smear their coats with the Penicillium strain for safety on their journey. They eventually arrived in Peoria, Illinois, to meet with Charles Thom, the principal mycologist of the US Department of Agriculture, and Andrew Jackson Moyer, director of the department’s Northern Research Laboratory. Thom corrected the identification of Fleming’s mold to P. notatum; it was initially identified as P. rubrum (1).

Thom also recognized the rarity of this P. notatum strain because only 1 other strain in his collection of 1,000 Penicillium strains produced penicillin. The strain that was eventually used in mass production was a third strain, P. chrysogenum, found in a moldy cantaloupe in a market, which produced 6 times more penicillin than Fleming’s strain. When a component of the media that Heatley used to grow the mold in England was unavailable, A.J. Moyer suggested using corn steep liquor, a waste product from the manufacture of cornstarch that was available in large quantities in the midwestern United States. With corn steep liquor, the investigators produced exponentially greater amounts of penicillin in the filtrate of the mold than the Oxford team had ever produced. Heatley remained in Peoria for 6 months to work on methods of growing Penicillium strains in large quantities. Florey headed east to interest the US government and multiple drug companies in penicillin production. The US government took over all penicillin production when the United States entered World War II. Researchers at drug companies developed a new technique for producing enormous quantities of penicillin-producing Penicillium spp.: deep-tank fermentation. This process adapted a fermentation process performed in swallow dishes to deep tanks by bubbling air through the tank while agitating it with an electric stirrer to aerate and stimulate the growth of tremendous quantities of the mold. Unprecedented United States/Great Britain cooperation for penicillin production was incredibly successful. In 1941 the United States did not have sufficient stock of penicillin to treat a single patient. At the end of 1942, enough penicillin was available to treat fewer than 100 patients. By September 1943, however, the stock was sufficient to satisfy the demands of the Allied Armed Forces (6).

Early in 1942, Florey and Heatley went back to England. Because of the shortage of penicillin supplies coming from the United States, the Oxford group still had to produce most of the penicillin they tested and used. In August 1942, Fleming obtained some of the Oxford group’s supply and successfully treated a patient who was dying of streptococcal meningitis. When the patient recovered, the cure was the subject of a major article in The Times newspaper in Great Britain, which named Oxford as the source of the penicillin. However, neither Florey nor Fleming was acknowledged in the article, an oversight quickly corrected by Fleming’s boss, Sir Almroth Wright. He wrote a letter to The Times expounding on Fleming’s work and suggested that Fleming deserved a “laurel wreath.” Fleming happily talked to the press. Florey not only did not speak with the press but prohibited any member of the Oxford team from giving interviews, leading many to erroneously believe that Fleming alone was responsible for penicillin.

The British government went to great lengths to prevent the means for producing penicillin from falling into enemy hands. However, news about penicillin leaked out. A Swiss company (CIBA, Basal, Switzerland) wrote to Florey requesting P. notatum. Concerned about responding, Florey contacted the British government. Agents attempted to track down where Fleming’s Penicillium cultures had been distributed. Fleming wrote, “During the past 10 years I have sent out a very large number of cultures of Penicillium to all sorts of places, but as far as I can remember NONE have gone to Germany” (7). Florey believed that, without the mold, no one in Germany could produce penicillin even though his publication had provided a “blueprint” for its small scale manufacture. Florey was wrong, and so was Fleming.

Fleming had sent a culture of Penicillium strains to “Dr. H. Schmidt” in Germany in the 1930s. Schmidt was unable to get strain to grow, but even though the Germans did not have a viable strain, other Europeans did.

The issue of a patent for penicillin was a controversial problem from the beginning. Chain believed that obtaining a patent was essential. Florey and others viewed patents as unethical for such a life-saving drug. Indeed, penicillin challenged the basic notion of a patent, considering it was a natural product produced by another living microorganism. The prevailing view Great Britain at the time was that a process could be patented, but the chemical could not. Merck (New York, NY, USA) and Andrew Jackson Moyer each filed patents on the process of penicillin production with no opposition. Eventually, at war’s end, British scientists were faced with paying royalties for a discovery made in England. The penicillin production at NG&SF turned out to be more than of historical interest. Because NG&SF had researched and developed their own penicillin using their own mold culture, P. baculatum, and used their own production methods, they were not embroiled in any patent clash; the marketing of their penicillin eventually increased penicillin supply and decreased prices.

Penicillin’s colossal effects led to the awarding of the Nobel Prize in Medicine and Physiology in 1945 to Fleming, Chain, and Florey. Penicillin was isolated from other microorganisms, which led to a new term, antibiotics. Using similar discovery and production techniques, researchers discovered many other antibiotics in the 1940s and 1950s: streptomycin, chloramphenicol, erythromycin, vancomycin, and others.

Lessons can be learned from the circumstances surrounding the discovery of penicillin. The US government’s successful takeover of penicillin’s production and the unprecedented cooperation among drug companies (and nations) should strongly encourage public/private partnerships as we search for additional effective antimicrobial drugs. In addition, despite their essential value in modern medicine, antibiotics are also the only class of drugs that lose their efficacy with large-scale use as bacteria develop antibiotic resistance. We now are struggling with resistant bacteria that cause infections that are virtually untreatable. Infections such as those occurring after transplantation and surgical procedures, caused by these highly antibiotic-resistant pathogens, are threatening all progress in medicine. Yet, drug companies, some of the same companies that helped develop penicillin, have nearly abandoned efforts to discover new antibiotics, finding them no longer economically worthwhile. The dry pipeline for new antibiotics has led the Infectious Diseases Society of America and others to call for a global commitment to the development of new agents (10). We also must expertly manage the drugs that are currently available. The noteworthy serendipity involved in the discovery of penicillin should remind us that new antibiotics are difficult to find and, more important, should make us mindful when using these limited medical treasures.